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Alzheimer’s Disease Current and

Future Perspectives
Edited by: Dr. Yildiz Dincer

ISBN: 978-1-63278-067-6

DOI: http://dx.doi.org/10.4172/978-1-63278-067-6-68

Published Date: February, 2016

Printed Version: February, 2016

Published by OMICS Group eBooks

731 Gull Ave, Foster City, CA 94404, USA.

Copyright © 2015 OMICS Group
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Preface

Alzheimer’s disease is a neurodegenerative disorder which is the most common form

of dementia in elderly people. The increase in average life expectancy during the 20th
century causes an increase in frequency of Alzheimer’s disease. The onset of disease is
insidious, takes more than thirty years. It becomes manifest with mild memory loss and
then progress with severe cognitive impairment and functional decline. Patients lose their
independence in performing daily activities and need a close caregiving. The caregiving is
a stressful responsibility and problems such as sleeping difficulties, fatigue, anxiety and
depression may frequently develop in caregivers. Socio-economic cost of Alzheimer’s disease
is devastating. The cause of the disease is not fully undestood yet and there is no effective
curative treatment. Current medications for Alzheimer’s disease slow disease progression
but cannot stop underlying degenerative process. This book is purposed to provide an
overview for suggested pathological mechanisms, diagnosis and current management of
Alzheimer’s disease as well as emerging therapeutic approaches.

Yildiz Dincer
Professor Of Medical, Biochemistry

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About Editor

Prof. Yildiz Dincer (PhD) is senior scientist in Istanbul University Cerrahpasa Medical
Faculty, Department of Medical Biochemistry, Istanbul TR. She received her master degree
(1996) and PhD (2000) from the same department. Dr. Dincer was a fellow at Imperial
Research Fund-Clare Hall Laboratories, UK in 1999, and has gained experience in the field
of DNA repair by working in the team of Dr. Tomas Lindahl who shared the 2015 Nobel Prize
in Chemistry for work on DNA repair. Dr. Dincer maintains an active research program
studying on oxidative DNA damage, DNA repair/apoptosis, antioxidants and epigenetics.
Dr. Dincer has published many articles and book chapters. She has served as the editor
of various edited collections on topics such as iron deficiency, chemical carcinogens,
chemotherapeutics and epigenetics. Dr. Dincer lives with her husband in Istanbul, Turkey.

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Acknowledgement
I would like to thank Professor Aynur Özge for not only contribuing this book as author but
also for her efforts in partipication of other authors.

IV
 Introduction to the eBook
Over the past few decades global prevalence of Alzheimer’s disease is increased and it
became a major public health problem. Millions of elderly population are suffering from
Alzheimer’s disease worldwide. Many efforts have been made aiming to prevent Alzheimer's
disease due to its rising prevalence, the lack of a curative treatment and its high socio-
economic cost. Although the study of Alzheimer's disease is moving ahead rapidly, cause
of the disease has not been fully clarified yet. Alzheimer's disease is a slowly progressing
brain disorder characterized by loss of synapses and neurons in cerebral cortex and in
certain sub-cortical regions which leads to memory impairment, cognitive decline, and
eventually death. The majority of Alzheimer’s disease cases are sporadic. This form of
disease is known as late-onset Alzheimer's disease, and is seen in cases older than 65
years. The rare and inherited form of disease is known as familial or early-onset Alzheimer's
disease. It is seen in cases younger than 65 years, sometimes as early as the mid-20s.
The diagnosis of Alzheimer's disease may be delayed or missed, because early symptoms
develop gradually and are often associated with the normal aging process; the symptoms
can mimic symptoms of various disorders such as vascular dementia, depression or brain
tumor; there is no early diagnostic tools based on quantitative biochemical markers.
Age, female gender, low education level, family history, major depression, head injury,
diabetes mellitus, hyperlipidemia are potential risk factors for Alzheimer's disease. The
hallmarks of the disease are extracellular neuritic plaques composed of amyloid beta
fibrils and intracellular neurofibrillary tangles composed of hyperphosphorylated tau
protein. The pathophysiology of Alzheimer's disease is highly complex and multifactorial.
Oxidative stress, neuroinflammation, metal dyshomeostasis, mitochondrial dysfunction,
insulin resistance and insulin deficiency in the brain are suggested as potential underlying
mechanisms of Alzheimer's disease. The current medications (acetylcholinesterase
inhibitors, glutamate N-methyl D-aspartate antagonist) do not reverse disease but can slow
disease progression. Investigations have focused on reducing the amyloid beta plaques,
amyloid beta aggregation/toxicity and tau aggregation. Different therapeutic approaches
including vaccination, anti-inflammatory agents, cholesterol-lowering agents, antioxidants
and hormone therapy are under investigation. As the disease progresses patients
become fully dependent on caregivers. Caregivers of Alzheimer's patients are usually family
members. Caring for someone with Alzheimer's is a stressful life event and caregivers are
under high level of emotional and physical stress. As the loved one's cognitive, physical,
and functional abilities diminish, nearly all caregivers experience sadness, anxiety,
exhaustion, loneliness, social isolation, sleeping difficulties, problems with the family and
at work which may lead health problems. The awareness about this issue, social and
psychological support and caregiver education programs are helpful to alleviate caregivers
stress.
The better understanding of Alzheimer’s disease provides a new perspective in AD
management, I hope this book will be helpful for the clinicans, psychologists, medical and
graduate students, health-care professionals, caregivers, researchers and other scientists
pursuing the biological basis of Alzheimer disease.

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Sl no Table of Content Page no

1 Clinical Aspect of Alzheimer’s Disease 1-22
2 Pathogenesis of Alzheimer’s Disease 23-45
Current and Future Therapeutic Approaches and Management
3 46-60
of Alzheimer’s Disease
Common Medical Problems in Patients with Alzheimer's
4 61-67
Disease
5 Nutritional Considerations in Patients with Alzheimer’s Disease 68-79
Caregiver Education and Support studies for Alzheimer’s
6 80-88
Disease
7 Emerging Therapeutic Approaches 89-100
8 Future Perspective 101-106

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Clinical Aspect of Alzheimer’s Disease

Osman Özgür Yalın1, Kahraman Kıral2, Nevra Öksüz3 and Aynur Ozge4*
1
Istanbul Research and Education Hospital, Department of Neurology, İstanbul,
Turkey
2
Çağ University, Department of Psychology, Yenice-Mersin, Turkey
3
Samandağı Goventment Hospital, Department of Neurology, Hatay/Turkey
4
Mersin University School of Medicine, Department of Neurology, Mersin, Turkey

*
Corresponding author: Prof. Dr. Aynur Ozge (MD), Mersin University School of
Medicine, Department of Neurology, Mersin, Turkey , E-mail: aynurozge@gmail.com
or aozge@mersin.edu.tr

Abstract
This chapter is about the giving some general information of Alzheimer’s Disease (AD). As
a most common type of dementia, it is not only most known causes but also most important
burden on our future. Epidemiological data shows us AD is the third most important
health care problems in the budget of developing countries with a growing importance of
bio-psycho-social aspect. We discussed definition of dementia disorders including AD with
supported developing diagnostic criteria. This chapter also included recent advances at
biologic markers of AD brought new diagnostic sets. Mild cognitive impairment has been
taken a specific subtitle in this chapter. The readers also found some important hints
for comparison of new sets of diagnostic criteria. This chapter included a comprehensive
summarized data about the known risk factors of AD. Changing clinical faces of AD has
been given as a concept explanation. This chapter will finalize a reference list for additional
reading.

Keywords: Alzheimer’s Disease; Dementia; Diagnostic Criteria; Mild Cognitive Impairment

Clinical Aspect of Alzheimer’s Disease
Definition of Alzheimer’s Disease
Alzheimer’s Disease (AD) is a neurodegenerative brain disease of elderly and the most
common known cause of dementia. It is characterized by a progressive decline in based
on memory, language, thinking, behavior and other cognitive skills that affect to perform
daily living activities. In Alzheimer’s disease, the brain cells themselves degenerate and die,
causing a steady decline in mentioned cognitive, behavioral and daily living functions. AD
is devastating not only for patients, but also for the caregivers, families and community [1].
Definition of dementia
Dementia is a brain disorder-usually in chronic or progressive nature- in which there
is disturbance of multiple higher cortical functions, including first in memory, thinking,

1
language, visuospatial, and judgment. Cognitive impairment interferes with independence
in daily living activities. Social behavioral, psychosocial impairment could proceed to
dementia syndrome or could become a part of disease by course [2]. AD is the most common
type of dementia; especially for older ages –more than half of the cases- and is not only a
clinical phenomenon but is a definition of a distinct clinico-pathologic entity more than one
century. The term of AD refers to a distinct ongoing pathologic process including preclinical,
mild cognitive symptomatology and AD dementia phases [3]. In spite of well-defined unique
pathological hallmarks of AD- beta-amyloid plaques and neurofibrillary tangles at specific
localizations with e progressive nature- phenotypic presentation of disease could diverse
individually. The diagnosis of dementia is mostly based on detailed history of patients’ and
associates, clinical examination, laboratory and neuro-imaging investigations are mostly
suitable to rule out secondary causes. Current advanced biological markers (magnetic
resonance and PET imaging techniques and Cerebrospinal Fluid (CSF) investigations) also
could help to diagnose dementia and AD, but their role at daily clinical practice is still
questionable. Although the term of dementia refers to impairment at multiple domains
of cognition, isolated deficits are frequently present as early manifestations of ongoing
degenerative process [4-6].
Diagnosis of dementia
Clinical examination of a patient referred to the neurologist for possible dementia should
cover a broad range of possibilities. The spectrum of admitting complaints of patient could
be various including: memory, behavior or personality alterations, alone or together with
each other. The other part could present with neglect of symptoms by the patient and
relatives may have noticed symptoms. Relatives or patients could describe impairment of
daily living activities. A clinician should firstly differentiate mimics and reversible causes of
dementia before final diagnosis of degenerative dementia (please refer to Table 1). This has
significant importance from many aspects; first he/she should diagnose treatable conditions
and second should differentiate static, non-progressive neurocognitive conditions. Common
causes of dementia-like syndromes (sometimes defined as pseudo-dementia) are depression,
delirium, drug side effects, thyroid problems, certain vitamin deficiencies and excessive use
of alcohol and drugs [1-5]. Summarized list of potential secondary causes of dementia has
been given at Table 1.
1 Vascular dementia (multiinfarct dementia, subcortical ischemic vascular events, strategic infarct, CADASIL, etc)
2 Normal Pressure Hydrosephalus
3 Wernicke-Korsakoff Disease
4 B12 vitamine deficiency
5 Hypothroiditis
6 Chronic hepatic disorders
7 Toxic agents (organic solvents, drugs, etc)
8 Herpes encephalitis
9 Neurosyphilis
10 Chronic meningitis
11 Chronic subdural hematoma
12 Neoplastic and paraneoplastic disorders
Table 1: Potential secondary causes of dementia.
Dementia diagnosis process includes a practical systematic approach at first step of
examination:
1. Medical and neurological history
2. Neurocognitive/behavioral history
3. Toxic and nutritional risk factors
4. Vascular risk factors
5. Physical examination

2
 We strongly propose medical and neurological history as first step of evaluation. Full
medical history should be obtained. In the situation of cognitive complaints are present
as a part of another systemic disease, if we do not diagnose underlying disease first, all
consequent steps and investigations will only move away us from correct possibly treatable
disorder. For example a patient with forgetfulness complaint could not associate his/her
sleep apnea or snoring if clinician does not ask. Frequent apneas could cause objective
cognitive deficits and impairment at daily performance as a result of sleep deprivation. The
clinician should evaluate carefully other signs of systemic disorders, such as endocrine
disorders, malignancy, and chronic infections [2,3].
Neurocognitive/behavioral assessments cover short mental examinations and detailed
neuropsychological evaluations. This part of examination also should begin with detailed
history obtaining. History of past disease should cover: cerebrovascular disease, epilepsy,
repeated head trauma, past intracranial operations, current or past infectious disease
history, psychiatric diseases, especially depression, psychosis, behavioral changes. But it
should be remembered that depressive symptoms could occur at early stages of dementia [2,3].
Toxic and nutritional risk factors are also important to assess. Alcohol abuse,
gastrointestinal surgery or malabsorbtion disorders, vitamin deficiencies, to be exposed
to pesticides and heavy metals should be investigated. Vascular risk factors should be
evaluated specifically; they have importance not only at diagnosis of dementia but also to
determine dementia type (vascular dementia, AD differentiation etc.) [2,3].
Physical examination could provide systemic involvement signs for differential diagnosis
of focused potential secondary causes of dementia. Neurologic examination could support
focal neurologic involvement or movement disorders signs and could add important points
to clinician. After the diagnosis of dementia one should decide final diagnosis of AD or other
dementia syndromes. Although AD have characteristic clinical features, clinical variations
are common. This heterogeneity complicates diagnostic accuracy, and correct diagnosis is
critical to advancing research. It has been discussed strengths and weakness of the major
definitional approaches and made recommendations for improving diagnostic precision
[2,3]. Early detection of AD in its clinical course has proven to be an important goal since
description of disease. Although we have advanced research and current biological and
neuroimaging techniques; early diagnosis of disease is remaining challenging. AD must be
distinguished from other dementia syndromes, including vascular dementia, fronto-temporal
dementia and other dementia syndromes. The key features to differentiate AD from others
are based to neuropsychological profile of patient examination, and the most important part
of the diagnostic sets is still based on clinical examination. Optimal clinical criteria should
allow for clinical variability in symptoms based on the patients’ socio-cultural background,
language and intelligence. Although the newly proposed criteria include biomarker evidence
and expected to enhance pathophysiological specificity of the diagnosis of AD, the core
clinical criteria will continue to be the cornerstone of the diagnosis in clinical practice [2,3].
The most commonly used diagnostic tools of AD are DSM criteria and NINCDS-ADRDA
criteria for several decades [2,7]. Recently International Working Group (IWG) and National
Institute on Aging along with the Alzheimer’s Association (NIA-AA) developed new diagnostic
criteria. And DSM-V published at 2013 and revised AD and dementia criteria. It has been
summarized and compared IWG, NIA-AA and DSM-5 diagnostic criteria at below [7-11].

IWG –Criteria
Dubois and colleagues developed new criteria at the scheme of a clinic-biological disease.
New criteria addressed several important aspects:
1) the diagnosis could be made at an living individual without biopsy confirmation,
2) there is no need to use ‘probable AD’ because other diseases could be excluded with
biomarkers, and disease biology could be demonstrated with biological markers,
3) the same clinic-biological defining could be used at every stage of disease, even for
non-demented individuals

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 4) several biomarkers could suppose diagnosis and fulfill criteria
5) in the IWG concept of Mild Cognitive Impairment (MCI) is abandoned. The IWG-2
criteria published at 2014 and aimed to simplify approaches with recent advances.
Population-based studies are needed to assess reliability of new criteria at clinical
practice, but rapid progress in the field of AD has been brought necessity of new
criteria continuously.
Workgroup proposed classification as; (1) Probable AD dementia, (2) Possible AD dementia, (3) Probable or possible AD
dementia with evidence of the AD pathophysiology (intended for research purposes). Probable AD dementia. Meets criteria for
dementia
1 Insidious onset (gradual onset over months to years)
2 History of worsening of cognition by report or observation
Initial and most prominent cognitive deficits. The most common syndrome feature is amnestic presentation, but non-
3
amnestic presentation could be observed (language, visuospatial, executive domains)
Clinical features are not pointing another diagnosis. Working group also proposed ‘Probable AD dementia with increased
5 level of certainty’ subtitle and adding feature of documented cognitive decline or being a carrier of a causative AD genetic
mutation (APP, PSEN1, or PSEN2)
Possible AD dementia Clinical features meet the core clinical criteria in the terms of the nature of the cognitive deficits for
6
AD dementia
Atypical course. Sudden onset, or insufficient historical detail or insufficient objective documentation of progressive
7
decline
Etiologically mixed presentation. Concomitant cerebrovascular disease or features of Dementia with Lewy Bodies or
8
evidence for another neurological disease or a non-neurological medical comorbidity or medication use.
Probable AD dementia with evidence of the AD pathophysiological process. Working group does not advocate the use of
9
biomarkers for routine diagnostic purposes.
10 The major AD biomarkers may be broken into two classes based on the biology.

Table 2: Diagnostic criteria of IWG for AD [2].

NIA-AA Diagnostic Criteria

In the 1984 [8-mckhann] a group reported NINDS-ADRDA criteria and diagnostic criteria
have been widely reliable for the diagnosis of probable AD. Criteria have had a sensitivity
of 81% and specificity of 70% and have been widely used in clinical trials and research.
In 2007, the International Working Group (IWG) developed new criteria; subsequently at
2011 a new group (NIA-AA) revised criteria of NINDS-ADRDA in the light of accumulated
evidence [9- Dubois,10-McKhann]. Both of them goaled to extend criteria to cover biologic
markers and aimed to cover all stages of disease from the asymptomatic phase to advanced
stage of AD. The NIA-AA classified AD at the three phases: preclinical phase, mild cognitive
impairment due to AD, and dementia due to AD.
NIA-AA criteria first described dementia-core clinical criteria. Because there are many
causes of dementia, they first outline all cause dementia:
1 Interfere with the ability to function at work or at usual activities; and
2 Represent a decline from previous levels of functioning and performing; and
3 Are not explained by delirium or major psychiatric disorder;
Cognitive impairment is detected and diagnosed through a combination of (1) history-taking from the patient and a
4 knowledgeable informant and (2) an objective cognitive assessment, either a ‘bedside’ mental status examination
or neuropsychological testing.
The cognitive or behavioral impairment involves a minimum of two domains (including memory, thinking,
5
visuospatial abilities, language, behavioral).

Table 3: Dementia diagnostic criteria at NIA-AA.

MCI is separated from dementia with preserved daily living activities. MCI diagnosis is
defined as a clinical judgment and defines daily complaints of the patient obtained from the
patient and an informant.

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Dsm-5 Criteria
DSM-5 is the latest edition published at 2013. DSM-5, classifies dementia as
neurocognitive disorder (NCD) [7]. Clinical diagnosis of dementia included minor NCD and
major NCD. Minor NCD is another description of Mild Cognitive Impairment (MCI) defined
by Peterson et al. To meet DSM-5 criteria for a mild NCD, an individual must have evidence
of cognitive decline, but it does not interfere with daily living activities (DSM-5).
Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains
1
(complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:
Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in
2
cognitive function; and
A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing
3
or, in its absence, another quantified clinical assessment.
The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with
4
complex instrumental activities of daily living such as paying bills or managing medications).
5 The cognitive deficits do not occur exclusively in the context of a delirium.
The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder,
schizophrenia)

Table 4: Major and Mild Neurocognitive Disorders diagnostic criteria.

Mild Neurocognitive Disorders diagnostic criteria

A. Evidence of modest cognitive decline from a previous level of performance in one or
more cognitive domains (complex attention, executive function, learning and memory,
language, perceptual motor, or social cognition) based on:
1. Concern of the individual, a knowledgeable informant, or the clinician that there has
been a mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by
standardized neuropsychological testing or, in its absence, another quantified clinical
assessment.
B. The cognitive deficits do not interfere with capacity for independence in everyday
activities (i.e., complex instrumental activities of daily living such as paying bills or
managing medications are preserved, but greater effort, compensatory strategies, or
accommodation may be required).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g., major
depressive disorder, schizophrenia).
Major or Mild Neurocognitive disorder Due to Alzheimer’s disease
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder
B. There is insidious onset and gradual progression of impairment in one or more
cognitive domains (for major neurocognitive disorder, at least two domains must be
impaired).
C. Criteria are met either probable or possible Alzheimer’s disease as follows:
For major neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if either of the following is present; otherwise,
possible Alzheimer’s disease should be diagnosed.
1. Evidence of a causative Alzheimer’s disease genetic mutation from family history or
genetic testing
2. All three of the following are present:
a. Clear evidence of decline in memory and learning and at least one other cognitive
domain (based on detailed history or serial neuropsychological testing).
b. Steadily progressive, gradual decline in cognition, without extended plateaus.
c. No evidence of mixed etiology (i.e., absence of other neurodegenerative or

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 cerebrovascular disease, or another neurological, mental, or systemic disease or
condition likely contributing to cognitive decline).
For mild neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if there is evidence of a causative Alzheimer’s
disease genetic mutation from either genetic testing or family history.
Possible Alzheimer’s disease is diagnosed if there is no evidence of a causative
Alzheimer’s disease genetic mutation from either genetic testing or family history, and all
three of the following are present:
1. Clear evidence of decline in memory and learning.
2. Steadily progressive, gradual decline in cognition, without extended plateaus.
3. No evidence of mixed etiology (i.e., absence of other neurodegenerative or
cerebrovascular disease, or another neurological or systemic disease or condition
likely contributing to cognitive decline).
D. The disturbance is not better explained by cerebrovascular disease, another
neurodegenerative disease, the effects of a substance, or another mental, neurological,
or systemic disorder.
Imaging of AD: Definite AD diagnoses requires autopsy confirmation. It is difficult to say
exact diagnose in early stages of AD. At this point neuroimaging studies and biomarkers make
it easier. Current diagnosis of AD is made by clinical, neuropsychological and neuroimaging
assessments. The MRI/CT in AD generally provides to measure volume changes in
characteristic locations in brain which makes a diagnositic accuracy in late phases of the
disease. Therefore there are developing new approaches to detect AD in early stages. In
MRI/CT mesial temporal lobe atrophy including hippocampal and parahippocampal region,
medial temporal atrophy and parietal atrophy especially in the interhemispheric surface
of the parietal lobe is seen [11-jagust]. In CT diffuse cerebral atrophy with enlargement of
the ventricles is seen. Also hippocampal atrophy in CT is associated with AD. But normal
healthy individuals and some patients with dementia may have no cerebral atrophy. CT is
not clinically useful in the primary diagnosis of the disease. The sensitivity and specificity
of CT is 81% and 67% [12]. Dilatation of the perihippocampal fissure may be a useful
radiologic marker for diagnosis of AD with CT, with a predictive accuracy of 91% [13].
The sensitivity and specificity were approximately 90% with MRI [14]. In MRI hippocampal
atrophy (about 50%), enlargement of the temporal horns, third and lateral ventricles is seen
[14,15]. Volume changes of the hippocampus, amygdala, cingulate gyrus, temporal horn,
lateral ventricles and basal forebrain provides a prediction rate of 77%. Functional MRI
(fMRI) techniques can be used to measure cerebral perfusion and structural imaging can be
done. Activational fMRI studies have included Blood Oxygenation Level–Dependent (BOLD)
imaging, and fMRI activation in the hippocampal and prefrontal regions is decreased in AD
[16]. The MRI techniques are sensitive and specific in differentiating AD from normal aging
and other dementias. And also can be used to detect asymptomatic or presymptomatic
individuals. MRI findings of hippocampal atrophy are highly associated with AD but the
specificity is not well established. Sensitivity is about 77%, and specificity is 80% [17].
SPECT is most commonly used for blood-flow measurement. SPECT isotopes have an
average half-life of 6-12 hours and variable. This limits the use of SPECT. In AD SPECT is
not used to assess AD, is used for diagnosing assessment of the disease.
SPECT studies of blood flow showed functional reductions in the posterior temporal
and parietal cortex. Reductions of cerebral blood flow (CBF) and oxygen use is seen in the
temporal and parietal neocortex region in AD. Reduction of glucose metabolism is seen in
the posterior cingulate cortex [18, 19].
Regional CBF (rCBF) were lowest in the hippocampus, the highest in the striatum,
thalamus, and cerebellum. A positive SPECT scan may show the probability of Alzheimer
disease by 30%, and a negative scan may show the absence of Alzheimer disease by only

6
10% [20]. SPECT scan studies have sensitivity and specificity of 80-90%. In one study, using
quantitative SPECT scanning reported a 63% sensitivity and an 87% specificity. Using
inhaled xenon-133 (133 Xe) and injected technetium-99m [99m Tc] hexamethylpropyleneamine
oxime, researchers reported a sensitivity of 76% and a specificity of 73% [21].
PET scanning provides noninvasive measurement of cerebral blood flow, metabolism,
and also receptor binding. Evaluation of pathogenesis, diagnosing and monitoring of the
disease’s progression is possible with PET scanning [22]. Carbon-11 (11 C), fluorine-18 (18 F),
or oxygen-15 (15 O) are generally used as tracers because of having short half-lives thus the
subjects are not exposed to prolonged radiation [22]. The most common one used for PET
scanning in AD is glucose with [18 F] FDG. FDG-PET is effective method for early diagnosing
and differentiation of AD from other types of dementia. Also is used to detect individuals
even before the onset of symptoms. In AD temporoparietal glucose hypometabolism is
characteristic. In late phases of the disease frontal involvement may be seen [23]. Entorhinal
cortex hypometabolism on FDG-PET has predictive value in the progression of disease.
The identification of asymptomatic individuals by PET scanning will have a major role in
the treatment of AD [24]. PET scanning with ligand PK11195 labeled with11 C, or (R)-[11 C]
PK11195, showed increased binding in the entorhinal, temporoparietal, and cingulate
cortices in AD. PET scan findings match histopathological reports of Aβ accumulation in
brain areas [25].
PET scanning is more sensitive than SPECT scanning. In AD FDG-PET has a sensitivity
of 94% and a specificity of 73% [26]. Developing a specific tracer for Aß plaques may
increase the sensitivity of PET scanning in early stages of AD in the future. Florbetapir
F 18 (AMYViD), flutemetamol F18 injection (Vizamyl) and florbetaben F 18 (Neuraceq) are
also the new agents approved by FDA and studies of these agents have been going on [27].
Study of the dopamine transporter (DaTScan) is another technique used for differentiating
AD from Lewy Body Dementia (LBD) not diagnosing AD.
Biomarkers of AD: Molecular mechanisms of AD and dementia are still completely
unknown and biomarkers remain reserved to search. There are several studies have begun
to target prevention of the disease at the early stages. There are no simple tests for AD or
dementia. Complete clinical neuropsychological assessment is still the only way to make a
correct diagnosis of preclinical stage of AD. On the other hand, neuroimaging techniques
and research of biomarkers for diagnoses developed rapidly in the past decade. But
consequently the value of biomarkers is not high enough and for now it is not possible to
use them in screening. Biological determinants of AD appear more complex. It may remain
less valuable in the next 10 years [2,3].
CSF biomarkers: In cerebrospinal fluid (CSF), total tau and Aβ levels are the most
promising and informative biomarkers of AD. CSF tau level is increases because of its
releasability from damaged and dying neurons. Aβ1-42 levels reduce in CSF of AD because
of its insoluble plaques accumulation in the brain. The combination of increased CSF
concentrations of t-tau and p-tau and decreased concentrations of Aβ1-42 can be used as
a pathological CSF biomarker for AD. Detection of reduced Aβ1-42 level has the greatest
sensitivity value 96.4% and the diagnostic specificity is 76.9%. On the other hand the
specificity for t-tau is 92.3% with the sensitivity of 69.9-80.6%. But the ratio of t-tau/Aβ1-
42
, the sensitivity is 85.7% and specificity is 84.6%. Consensus reports recommend that
informative biomarkers of AD should have a sensitivity and specificity of more than 85% [28].
Plasma biomarkers: In some studies peripheral venous system of AD patients were
searched to identify diagnostic biomarkers. But it still remains a question if biomarkers
will be found for AD. Serum α-2-macroglobulin (α-2-M), albumin, α1-antichymotrypsin,
Complement Factor H (CFH) are previously shown to be potential biomarkers. Serum
albumin and immunoglobulin levels showed different findings and also have been examined
in CSF and the findings were controversial. Some of them showed relation increase of

7
immunglobulins and albumin in CSF and serum, and some of them not [29]. Both α-2M and
its receptor LRP have been linked with Alzheimer’s disease, but there is not supportive study
of an association. A proteinase inhibitor, α1-antichymotrypsin, has also been suggested as
a blood-based biomarker of Alzheimer’s disease [30]. The CFH precursor was shown with a
significant increase in AD but not in other neurodegenerative disorders. Also CFH is found
to be in relation of severity of the disease. CFH was previously shown in plaques in AD
without an increase in CSF. Elevated clusterin levels in plasma, but not in CSF is found in
relation with cognitive decline. elevated plasma clusterin levels is a risk for rapidly cognitive
decline. Plasma clusterin levels may be usable prognostic marker for AD [31,32]. Exosomal
miRNAs was searched in AD patients’ plasma. Subgroups of miRNAs especially miR-342-3p
showed difference whereas the total amount of miRNAs did not differ. Integrating this data
with other biomarkers of AD may provide information and can be used as a biomarker [33].
All these plasma biomarkers may help us to differentiate AD from other neurodegenerative
disorders in the future. But it must be easier to use in routine clinical practice. However,
plasma based biomarkers are not feasible in AD because of not being specific for now.
AD Mimics Clues
Anxiety and depression Neuropsychometricprofile,Psychiatrics consultation
Vascular cognitive impairment MRI, CT
Transient epileptic amnesia EEG and anamnesis
Transient global amnesia Anamnesis and neuroimaging
Metabolic diseases Laboratory investigations
Space-occupying lesions MRI, CT
Infections MRI, CT and Lumbar punction
Korsakoff’s psychosis Anamnesis, MRI, Laboratory Investigations
Table 5: Important clues differentiate AD from other type of dementia syndromes. [34].

DSM-V NIA-AA
Interfere with daily and occupational activities + +
Daily living activities + +
Instrumental living activities + +
Decline from previous levels of function + +
There is no major psychiatric disorder + +
Cognitive decline is detected with objective assessment + +
Cognitive decline is reported with a relative + +
Cognitive impairment at multiple domains + +
Memory
Complex tasks
Language
Executive functions
Visuospatial functions
Amnestic presentation + +
Non-amnestic presentation - +
Insidious onset + +
Gradual progression + +
Cerebrovascular disease temporally related with symptoms - +
Absence of clinical evidence of other dementia syndromes - +
Documented cognitive decline - +
Evidence of a causative genetic disorder (APP, PSEN1 or PSEN2) + +
Evidence of the AD pathophysiological process , Brain amyloid-beta (Aβ) protein
- +
deposition (low CSF Aβ and positive PET amyloid imaging)
Biomarkers of neuronal degeneration (CSF tau, decreased, FDG uptake on PET in
- +
temporo-parietal cortex, and disproportionate atrophy on structural MRI

Table 6: Comparison of diagnostic criteria [34].

8
Epidemiology, Potential Causes and Risk Factors of AD
Alzheimer’s Disease prevalence term refers to the proportion of AD people in a population
at a given point in time. Incidence refers the number of new cases per year in a population.
Since population aging has become a worldwide universal actuality, it’s expected to increase
dementia people over years. United Nations Aging Program and the US Centers for Disease
Control and Prevention reported that the number of older people will doubled and reach
near 1 billion by 2030, and the proportion of older people being increased from %7 to %12
[35,36]. The largest increase is expected to occur at developing countries. Cost of dementia
is estimated at 818 million dollars, and expected to rise at 2 trillion dollar level at 2030.
Prevalence of AD
World Alzheimer Report published at 2015 and largely reviewed global impact of dementia
by a consensus of authors. Living dementia objects are estimated to increase from 46 million
at 2015 to 131.5 million at 2050. Economic impact of dementia will increase exponentially
over years and this will occur for especially developing countries. These new estimates are
12-13% higher than those made at 2009. Despite several limitations, meta-analyses have
yielded roughly similar age-specific prevalence of AD across regions. Much of the increase
through to 2050 is attributed to occur at low and middle-income countries (Figure 1). The
58 per cent of world dementia sufferers is living at low and middle–income countries today
and at 2050 this proportion is projected to reach %71. At 2015, the global prevalence of
dementia was estimated to be 5.2% in people aged over 60 years, with the regional prevalence
being 6.4% in America, 5.9% in Europe, 4.7% in Asia and 4.6% in Africa. The age-specific
prevalence of AD almost doubles every 5 years at +65 years aged population. In developed
countries, more than 1 in 10 older people (over 65 years old) is affected dementia related
symptoms [37]. There is similar prevalence of Alzheimer’s disease across the world and
covering %50-70 of all dementia patients [2]. Projections for growth in dementia population
are attributed to low-middle income countries. Although developed nations started from a
high prevalence but expected to experience only a moderate proportionate increase. This
trend is driven mainly by growth rates of population [38].

150

100
89.28
77.63
66.45
50 56.16
46.74
32.30 38.72
27.28
19.50 21.97 24.73 27.95 31.72 35.71 39.14 42.18
0
2015 2020 2025 2030 2035 2040 2045 2050

High Income Low and Middle Income

Figure 1: The growth in numbers of people with dementia in countries (Reprinted from World Alzheimer Report 2015).

Incidence of Alzheimer’s Disease

The pooled incidence rate of dementia among people 60+ years of age in the world was
17.3 per 1000 person-years [38]. The incidence rate of AD increases exponentially with age
(Figure 1 State of Art Figure 2). There have been some geographic variations in the incidence
of AD. Comparisons between European countries revealed geographical dissociation, and
the higher incidence rates being found among southern countries [39]. The incidence rates
of AD were reported highest at North America and Western Europe, and lower at Asia, Africa
and Latin America. In Europe and America peak incidence is among those 80-89 years,
in Asia it’s among those at aged 75-84, and in Africa among those aged 65-74 [38]. The
organization estimated over 9.9 million new dementia case each year worldwide, implying

9
one new case every 3.2 seconds. And includes 4.9 million new cases (49% of total) in Asia,
2.5 million (25%) at Europe, 1.7 million (18%) at Americas, and 0.8 million (0.8%) in Africa.
It’s important to follow incidence rates among countries, because it’s the most important
demonstrator of secular trends and mostly affected by changes in population exposure to
modifiable risk factors.
Global impact of dementia and AD
At the level of dementia sufferers, AD shortens life span and moreover it’s strongly
associated with functional disability and dependence. In a follow-up study at Sweden people
within over +75 years old people, more than half who developed functional dependence is
attributed to dementia and AD over a three years period [40]. AD is also strongly associated
with mortality. Helzner et al., [41], reported 3 to 6 years median survival time for newly
diagnosed AD patients. Since rapid increase in the number of dementia subjects, AD
will cause tremendous consequences for society. It was estimated that nearly half of AD
patients require high level of care at home or institutions. At developed countries long-term
institutional care will be the most main cost, whereas in developing countries home care
by relatives of patients is expected to be major source of care. The global economic cost of
dementia is estimated at 818 billion US dollars. This enormous sum is equivalent to Global
Domestic Product (GDP) of some countries like Turkey, Netherlands [38].

Potential Causes and Risk Factors of AD

AD is a multifactorial disease, as representative of neuro-degenerative diseases, including
Parkinson disease, Amyotrophic Lateral Sclerosis. There are genetic and environmental risk
factors described. The pathophysiologic alterations may begin more than 20 years before
clinical symptoms appear. Brain could compensate neuronal alterations for a long time and
continue normal functions without any symptom. Because of the complexity of brain, an
exact mechanism of symptomatology and threshold to symptoms occurs are still mystery. A
healthy brain includes about 100 billion neuron, each neuron have branching extensions,
accumulate nearly 100 trillion synapses. Synapses allow signals to travel through circuits
and creating cellular basis of higher cortical and subcortical functions. The pathological
hallmarks of AD are the accumulation of the protein Aβ at outside of neurons (beta amyloid
plaques), and accumulation of an abnormal form of the protein tau inside of neurons
(neurofibrillary tangles). Aβ accumulation is believed to cause synaptic transmission and
tau tangles are believed to cause block transport at neuron. Both of them resulted with
neuronal dysfunction, and eventually shared pathway is neuronal death, expansive cell
loss and shrinkage of brain. Here one should note that MCI, specifically amnestic form
is regarded as early clinical representation of AD but is not the beginning point of AD
pathological disease process. It’s unclear whether some are conversing to AD with time and
some of the living subject are never showing dementia or MCI clinical picture although have
pathological changes. Early diagnosis and intervention is very important to attenuate the
course of AD and decrease the burden on patients, care-givers and also health systems. For
the purpose of slowing the course of progress and preventing the disease, researchers have
been studying to identify its causes and risk factors [2,38].
Alzheimer’s disease Genetic factors
*Genetic mutations Dominantly inherited AD; APP, PRES1, PRES2
*Family History APOE4, unknown genetic mutations or shared Environmental factors
*Cardiovascular disease Diabetes Mellitus, Hypertension, Smoking, Hyperlipidemia, Obesity
*Psychosocial factors Lower education, social isolation, and mentally sedentary life
*Vitamin D deficieny
*Nutritional and dietary Folate, vitamin B12, and antioxidant deficiency
*Traumatic brain injury
Table 7: Summary of possible risk factors and protective factors for Alzheimer’s disease.

10
 Genetic Risk Factors: Genetically AD can be classified in two forms. (1) One of these
forms is characterized with early onset of disease (<60 years) and the term “familial” is
used to represents this form. (2) “sporadic” is used to identify late-onset AD ( ≤ 60 years)
and less or no familial aggregation [42]. Early-onset AD is dominantly inherited AD and is
pathology is related to mutations in one of three genes including Amyloid Precursor Protein
(APP), Presenilin 1 (PSEN1) or presenilin 2 (PSEN2) [43]. Amyloid hypothesis suggests that
amyloid-beta (Aβ) is generated from APP. Mutations in APP and presenilins alter the ratio
of Aβ species (increase Aβ42, more toxic form) and unbalance the generation and clearance
of Aβ. The accumulation of beta oligomer leads the accumulation of neurofibrillary bundles
which are responsible for synaptic dysfunction, axonal degeneration and neuronal loss
[44]. Increased cortical amyloid load was shown in almost all patients with AD. Moreover
it was found in MCI patients and healthy elderly subject (over 70 years old) with the ratio
respectively as 50% and 20-30% [45]. Cortical amyloid load also increases the risk of
converting MCI to AD. For example a study revealed a 93% risk for MCI patients to convert
into AD over 3 years [46]. On the other hand, the most important known genetic risk factor
for AD (especially for sporadic form) is Apo lipoprotein E epsilon 4 (APOE ε4) alleles [47].
APOE gene have three forms-ε2, ε3, and ε4. Everybody carries two of them constituting an
allele and each from one parent. The most common form is ε3 form; having ε2 form could
decrease risk of AD. The ε4 is related with increased risk of AD, those who inherit two ε4
genes have a higher risk. APOE ε4 is expressed in more than half of patients [48] and
shows vary effect on AD. Previous studies revealed that the presence APOE ε4 decreases the
mean age and increases the risk for AD [49]. In particular, one APOE ε4 allele may increase
the risk for AD 2-3 fold, whereas two copies may increase the risk about 12 fold [50,51].
Pet imaging studies showed that ApoE deposited in neuritic plaques and neurofibrillary
tangles and is related to higher deposits of Aβ [52, 53]. Patients who carry APOE ε4 allele
represented higher brain Aβ deposits when compared to other APOE allele carriers [54].
This deposits increase the loss of dendritic spines [53]. The possession of APOE ε4 allele is
also associated with worse cognitive performance or cognitive decline in AD patients, MCI
patients or non-demented participants [55,57]. However, APOE ε4 allele does not guarantee
the developmental of AD. Some patients have no copies of APOE ε4 whereas some APOE ε4
carriers may have intact cognitive functions [58].
Genome-wide association studies have demonstrated other susceptibility genes with
lower impacts [59,60]. Recent Genome-Wide Association Studies (GWASs) tested several
genetic markers to determine the additional genotypes that may contribute to explanation
of AD pathology. There are some studies show that there could be an association between
AD pathology and some additional genetic variants including Clusterin (CLU), complement
Component Receptor 1 (CR1), and phosphatidylinositol binding Clathrin Assembly Protein
(PICALM) [61,62]. CR1 is a Receptor 1 (CR1) is a single chain type I transmembrane
glycoprotein. CR1 plays an important role in regulation of complement Cb3 protein which is
involved in complement system and important to protect against Aβ-induced neurotoxicity
[59]. CR1 risk allele has been associated with regulation of Aβ clearance in the brain and
shown a mediated effect on cognitive decline [63]. CLU, also known as apolipoprotein J,
also plays a role in clearance of Aβ from the brain. There is some evidence that shows
an association between increased CLU level in cortex and hippocampus and AD risk [61].
PICALM regulates the synaptic transmission and Aβ clearance, and in AD studies it was
shown that there is a link between CLU, PICALM and lower memory performance [62].

Known Non-Genetic Risk Factors of AD

Age
Advanced age is the strongest risk factors AD. Most of the patients are diagnosed at
age 65 years and older. Although people younger than 65 can be diagnosed (early-onset of
disease) these are rarer (less than %2 of subjects) [64]. Prevalence of AD shows an increase

11
with age and is doubled with every five year increase in age. Over the age of 85 years almost
one-third of people have AD. 10 years increases in age result decrease in many cognitive
performances such as memory, abstract thinking, set shifting and language [65]. However
advanced age alone does not cause the disease.
Family history Individuals with first-degree relatives have AD are more likely to develop
disease, both genetic and shared environmental factors could contribute to the familial
aggregation. Several candidate genes have been studied, including vascular-related genes,
cholesterol pathway and insulin degradation genes with inconsistent results.
However the mechanism of action of positive family history on AD pathogenesis is unclear.
One explanation can be made by attributing the relationship between family history and
APOE genotype. Approximately 45% of adult offspring of patients of AD carry ε4 allele and
this possession increase the risk of developing AD [66]. Moreover, not only ε4 allele but also
carrying ε3 allele substantially increases the risk of AD. Martinez et al., [67] found that risk
of AD for first-degree relatives of a patient is 29.2% for those who carry of ε3/ ε3 genotype,
46.1% for carriers of ε3/ ε4, and 61.4% for carriers of ε4/ ε4. Family history may influence
the effect of APOE 4. Johnson et al., [68] found less hippocampal activation in ε4 carriers
with positive family history when compared with ε4 carriers with positive family history.
Moreover this study showed that family history is a predictor of mesial temporal lobe (MLT)
activation independent of APOE genotype. Family history is also associated with alterations
in hippocampal region and white matter adjacent to hippocampus. This region is known as
one of first regions affected by AD pathology [69].
Mild Cognitive Impairment (MCI) MCI is a definition of objective cognitive impairment
with preserved daily living activities. MCI, particularly amnestic form is one of the major
risk factor to develop AD. It’s estimated risk is 16% per year rate of progression to AD [70].
Findings of another study showed a progression rate 41% after 1 year and 64% after 2
years [71]. In a review summarized results of studies points that the most important part
is clinical diagnostic criteria, different criteria could result with different rate [72]. This
high rate of conversation of MCI to AD promoted researchers to determine the factors that
contribute the progression of AD in MCI patients. Positron emission tomography studies
revealed that identifying some biomarkers is a valuable technique with high sensitivity and
specificity values for prediction of progression [73]. Especially 11C-Pittsburgh compound
B (11C-BİP) that binds amyloid fibrillary, studies indicated high risk for MCI patients. In
a meta-analysis 93% risk for conversation into AD over 1-3 years was estimated for MCI
patients with a positive amyloid PET scan [46]. It also should be noted that studies included
only amnestic form-MCI. Accumulated evidence also shows there are patients whom did
not progressed to AD or restored. At 2011 proposed criteria, in particular cases, MCI is
regarded as an early stage of AD.

Cardiovascular Disease Risk Factors

There is accumulated evidence suggesting that the health of cardiovascular and cerebral
vascular structure is closely related with risk of developing AD. A healthy brain vascular
territory is mandatory for neuronal health. However alterations in brain vascular system
may cause neurodegenerative diseases such as AD. Cardiovascular dysfunctions have been
linked in several ways to increase the likelihood of developing AD. For example, cerebral
hypo perfusion reduced oxygen and glucose level in brain tissue. As a result of impaired
glucose level, reduced regional metabolic rate in temporal and parietal regions was found
in AD patients. Reduced concentration of glucose Transporter (GLUT) was showed by
autopsy studies and supported previous findings. Also toxic and metabolic disturbances
are also partially responsible to develop AD.Vascular pathologies such as atherosclerosis,
arteriosclerosis, cerebral amyloid angiopathy and, as well, Blood Brain Barrier (BBB)
dysfunction were linked to AD pathology. Especially dysfunction and structural changes in
BBB is associated with AD risk via reduced in clearance in of Aβ and increased in neurotoxic

12
molecules (as result of impaired energy supply) [74]. However, to control vascular modifiable
risk factors including blood pressure, cholesterol, and obesity could decrease the risk of AD.
Smoking and alcohol
Although earlier studies reported lower prevalence rates of AD among smokers, this
effect was due to selective survival bias. Following studies concluded that current smoking
associated with a 1.8 fold increased risk of AD [75]. A recent review of literature explored:
The cumulative body of research indicate that past and current smoking is associated with
an increased risk for AD, and there is no evidence demonstrating that nicotine could provide
any protection from AD [76]. The findings of a meta-analysis revealed that smokers have
increased risk for AD s when compared with non-smokers. Smokers also showed increased
decline in their cognitive abilities [75]. Alcohol abuse can cause ‘alcoholic dementia’, and
heavy drinkers have also increased risk of AD at late life, especially among the APOE ε4
allele carriers [77]. Contrast, light-moderate alcohol consumption was frequently related
with a reduced incidence of AD [78-80]. However protective effect of mild-moderate alcohol
consumption is also controversial due to information bias. The effect of healthy lifestyle,
high socioeconomic status, and other dietary factors should be investigated. Indeed alcohol
consumption could also protective effect at cardiovascular diseases and dose-dependent
U-shaped relation of alcohol consumption and AD is seems mostly evident [81].
Body mass index, obesity
Obesity is assumed as a modifiable risk factor for dementia and AD, for a time. Body
mass index (BMI) is defined as body mass (weight in kilograms) divided by the square of
the body height (term of meters). A higher BMI at midlife is demonstrated with longitudinal
studies as a risk factor for future [82,83]. Anstey et al., [84] showed that mid-life BMI may
decline the onset age of AD. According to these results overweight and obesity groups all
have increased risk for AD. It also should be noted that obesity is associated with other
medical risk condition such as diabetes and hypertension. Thus as a risk factor obesity
may show a comorbid effect for developing AD. Contrast late life, especially after age 65 BMI
is reported inversely related with AD, thus, low BMI in late life was related to a higher risk
for AD. Late life low BMI and weight loss should not be interpreted an individual’s general
health and could be a result of some serious disorders including malignancy and dementia.
Blood pressure and hypertension
High blood pressure is considered as a risk factor for AD in several ways. Several
longitudinal studies revealed hypertension for long time, particularly uncontrolled high
blood pressure is related with increased risk of late-life AD [85,86]. Variability of blood
pressure is also related to cognitive dysfunction in AD patients. Lattanzi et al., [64] showed a
link between systolic blood pressure (SBP) and faster cognitive decline in AD patients. Other
studies also found a relation between SBP variability and white matter atrophy [87,88] In the
light of this information, reduced cognitive functions might partially ascribable to structural
changes in the brain stemming from white matter lesions. Hypertension history for a long
time is clearly a major risk factor ischemic lesions, stroke and vascular dementia and effective
treatment is protective against ischemic events, but also protective for late life dementia and
even AD. But studies, which are investigating late life blood pressure and association of
dementia inconsistent, many studies found no association. Some studies also showed low
blood pressure was related with higher dementia risk, but optimal blood pressure remains
unknown. Lastly some studies suggest a protective effect of antihypertensive treatment
against dementia [89]. Hoffman et al., [90] found significantly less Alzheimer pathological
changes in the Diabetes Mellitus, Type II.
Diabetes Mellitus (DM) is closely associated with cognitive decline in abilities such
as working memory, mental flexibility, abstract reasoning, attention etc., in elderly. The
mechanism underwent this process might partially ascribable to the relationship between

13
β-amyloid neurotoxicity, advanced glycosylation and altered insulin function [91]. Some
animal models support assumption. For example, Mooradian [92] showed reduced BBB
choline transportation in diabetic rats. On the other hand, population-based large studies
have shown consistently that type-2 diabetes increases the risk of AD with calculating
relative risk varying from 1.5-1.9. In a longitudinal study with follow-up more than 5 years
revealed that diabetes is strongest risk factor for AD and the risk is more prominent when
other vascular risk factors are present [93]. Meta-analysis of diabetes and AD risk estimated
relative risk of nearly 1.5 between type-2 diabetes and AD, and the risk increase by the
presence of smoking, APOE4, and hypertension. Association could reflect a long-term effect
of hyperglycemia or hyperinsulinemia on neurodegenerative changes in the brain.
Hyperlipidemia
Most cross-sectional studies have demonstrated that middle-aged hypercholesterolemia
is an independent risk factor for AD. But results of studies investigated dyslipidemia in late
life with AD have inconsistent results. A recent careful analysis of current literature has
shown no or controversial association between late-life dyslipidemia and AD risk, and no
beneficial effect of statin therapy [82].
Hyperhomocysteinemia (HHcy)
HHcy is a well-defined cardiovascular risk factor resulted from genetic and non-genetic
mechanisms. Both of mutations of regulating genes or deficiencies of vitamin cofactors of
homocysteine are potentially responsible from HHcy. Vitamin B12, folate and pyridoxine
are some of the cofactors have role in homocysteine metabolism. Many studies have
found association of plasma homocysteine with AD. And also in some studies HHcy at AD
population are reported related with vitamin cofactor deficiency and reverted with vitamin
supplements. In spite of this, epidemiologic studies have shown reversing of HHcy have not
effect at dementia course [82,85].
Vitamin D
Recent studies confirm that the low serum vitamin D is associated with AD and dementia.
Though vitamin D deficiency is common in older adults it’s important to establish effect of
deficiency to AD. The serum level of vitamin D3 is monitored by measuring 25-hydroxy
vitamin D3. The risk of cognitive decline reported markedly increases below a threshold
between 25 and 50 nmol/L. In a recent prospective population-based large study, patients
followed for up to 5.6 years. Researchers’ reports vit-D deficient patients had about a 51%
increased risk of dementia, whereas the increased risk for those who were severely deficient
was about 122%. And they report AD markedly increases at 25(OH) D concentration below
50 nmol/L [71]. But there is no evidence-documented benefit of Vitamin D replacement at
AD course. Well-conducted Randomized Clinical Trials (RCTs) to test the effectiveness of
vitamin D supplements against placebo in patients with AD are essentially needed at this
time [94,95].
Traumatic brain injury
Recent studies have shown that patients with Traumatic Brain Injury (TBI) have
significantly more Aβ accumulation in gray matter and striatum when compared with
control patients with no TBI history [96]. Similar results have also found in autopsy of
patients who die within hours following TBI [97]. Moreover, the type of Aβ formed by TBI
is Aβ42 that is closely related to AD. Although there are several evidence about Aβ in TBI
and AD patients, there are some doubt for the linkage between AD and TBI pathology. For
example, plagues in AD are predominantly found in elderly and develop slowly whereas
plagues in TBI patients develop in a short time after brain injury and can be found even in
children [98]. Other factors such as age, sex and occurrence of APOE polymorphism also
contribute to this linkage and increase the risk of developing AD after TBI. For example it is

14
known that ε4 allele cause poor recovery following TBI. Thus APOE ε4 carriers have higher
risk after TBI when compared to non-carriers [99]. In a recent review have been summarize
accumulated evidence. Retrospective studies report that history of traumatic brain injury is
related with increased risk of dementia, particularly at men. While prospective studies have
inconsistent results. There are also evidence suggesting extend of amyloid beta pathology
and intraneuronal tau pathology after brain injury. In addition CSF amyloid beta levels are
elevated after brain injury.
Education, social and cognitive engagement
People with fewer years of education have higher risk of AD than those with more
educated. In recent meta-analysis results consistently and strongly shown that those with
lower education had a higher risk for dementia, the pooled OR was 2.61% for prevalence
and 1.88 for incidence studies [100]. The ‘cognitive reserve’ hypothesis has been proposed to
explain this altitude [101]. Cognitive Reserve term refers to the ability to compensate the age-
related changes and pathology in the brain without signs of disease. It has been supposed
that brain networks are more efficient and have greater capacity with morphological changes
at synaptic and neuronal levels. Early mental and physical stimulation, throughout for
life course is thought to increase cognitive reserve and allowing to maintain functions in
old age. Some animal models contributed this hypothesis. Petrosini et al., [102] showed
that environmental enriched animal have changed brain chemistry, neural functioning and
increased synaptic connectivity. Gray matter volumes can be vary to the degree of CR level.
Increased gray matter volume of supramarginal gyrus and posterior cingulate cortex was
presented in AD patients with higher CR [103]. In addition to education, extensive social
networks, active engagement, and participation to intellectually stimulating activities could
lower the risk of AD.
Depression
The relation between AD and depression is complicated with whether depression is a
prodromal symptom of AD or a risk for later development of AD. But at last meta-analyses it
is supposed that depression is regarded as a risk factor to development of future AD. There
is lack of evidence about why depression and AD may be linked. There is increasing evidence
about possible role vascular diseases, and also about shared genetic susceptibility. On the
other hand, loneliness may contribute this link. It is known that feeling of loneliness increase
the risk of AD and loneliness individuals tend to perform worse cognitive performance [104].
Long-term inflammatory process is another proposed link about togetherness. Even though
there is no knowledge about shared pathophysiologic mechanisms, correct diagnosis of
depression at patients and appropriate treatment could decrease the risk of future dementia
[105]. Additionally, diagnosis of depression and management at MCI and AD subjects is
critical to improve quality of life, and could have positive effect at the course of disease for
all stages.

Behavioral and Psychological Symptoms of AD

Behavioral and psychological symptoms are recently defined shortly as neuropsychiatric
symptoms (NPS) and being recognized more commonly as an important part of AD those
are expressed throughout the course of disease. NPS have prominent impact on the Quality
Of Life (QOL) for both patients and caregivers. Indeed recognizing of NPS provided new
insight to pathophysiology of AD. Like we described depression as a risk factor of future AD,
concurrently depression is one of the major NPS at the course of AD. NPS of AD are thought
to be indicator of more extensive neurodegeneration, functional dependence and assumed
as predictive of poorer outcome [105,106]. Prefrontal subcortical limbic involvement is an
early feature of AD, thus could explain early and prominent behavioral symptoms, and NPS
become more prominent and problematic as AD progresses. Depression and apathy are
the most common NPS observe more than half of the patients. At the last decades lots of

15
measurement instrument developed to assess NPS at dementia subjects. Brief Psychiatric
Rating Scale, Multidimensional Observation Scale for Elderly Subjects and Neuropsychiatric
Inventory (NPI) are some of them. The NPI is the most commonly used questionnaire
evaluates 12 emotional behavior commonly observed in dementia, with the data collected
from a relative or caregiver. Items evaluated at NPI include: delusions, hallucinations,
agitation, depression, anxiety, apathy, irritability, euphoria, disinhibiting, aberrant motor
behavior, nighttime behavior disturbances, and appetite and eating problems [2,105].
Depression and apathy
Depression is commonly observed in the course of AD, with the prevalence of 25-75% and
the most common NPS with apathy. Variability between studies results from methodology.
A study showed 40% of AD patients showed depression symptoms during follow-up and
moreover concurrence of depression is reported as related with poorer prognosis. Studies
evaluating genetically shared mechanisms and pathophysiological processes related with
depression have inconsistent results. The clear point is that depression at the course of
AD is related with reduced cognitive capacity, QOL, and daily living activities. Treatment of
depression is expected to benefit depressive and cognitive symptoms. Apathy is commonly
exists with depression [106].
Apathy is defined as a loss of cognition, actions and emotions. Apathy is also could
be defined as loss of motivational aspects of life and is a predictive of poorer outcome
like other NPS of dementia. Apathy is the most common NPS occurred at the course of
AD, together with depression. Whether depression and apathy are distinct syndromes
remains controversial [107,108]. Reports at the European Alzheimer Disease Consortium
Study showed that apathy is the most common NPS during the course of disease with the
prevalence of 55.2%, followed with depression 36.7% prevalence [107].
Agitation and aggression
Agitation and aggression are generating significant danger to AD patients and caregivers.
They are also correlated with poorer outcome and strongly associated with intensity of
disease. Their prevalence increase with disease progression and more commonly reported at
males. Aggression is frequently linked to frontal serotonergic dysfunction. There is a strong
correlation between psychosis, delusions and aggression [107,108].
Psychosis
Psychotic symptoms are investigated at the items of hallucinations and delusions at
NPI. They are least NPS at early stages of AD but their frequency increases with disease
progression. They are most disturbing and treatment resistant features of spectrum of
NPS of AD. Like other NPS, their emergence represents more rapid progression. Aalten
et al., reported presence of delusions at 19.4 % and hallucinations at 9.1% of their study
population; although they are less frequent, authors conclude they are associated with the
highest level of total NPS. Neuroimaging studies suggest these patients have greater cortical
impairments and pathologic studies reveal that these patients have more prominent cortical
impairment than without psychosis AD patients. Psychotic symptoms are reported more
common at people with family history of AD, thus suggests the role of genetic susceptibility
[107,108].

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 eBooks

Pathogenesis of Alzheimer’s Disease

Zeynep Caliskan1,2 and Yildiz Dincer1,*
1
Department of Medical Biochemistry, Istanbul University Cerrahpasa Medical Faculty,
Istanbul, Turkey
2
Department of Biochemistry, Yeni Yuzyıl University Medical Faculty, Istanbul, Turkey

Corresponding author: Yildiz Dincer , Department of Medical Biochemistry, Istanbul

*

University Cerrahpasa Medical Faculty, Istanbul, Turkey, E-mail: yldz.incer@gmail.com

Abstract
Alzheimer’s Disease (AD) is an age-related progressive neurodegenerative disorder
characterized by progressive memory loss, cognitive impairment and functional decline.
Many efforts have been directed to prevent AD due to its rising prevalence and the lack
of an effective curative treatment. AD is a multifactorial disease and various mechanisms
have been suggested to play key role in the pathogenesis. Increased understanding of the
molecular mechanisms underlying AD pathogenesis provides a basis for development of
new, effective therapeutic strategies to prevent onset and/or progression of AD. This chapter
provides a brief overview about the pathologic mechanism linked to AD.

Keywords: Alzheimer’s disease, oxidative stress, diabetes mellitus, neuroinflammation,

epigenetics, sirtuins, microRNAs

Hallmarks of Alzheimer’s Disease: Amyloid Plaques and Neurofibrillary

Tangles
The key neuropathological changes observed in AD brain are extracellular senile plaques
that are mainly composed of amyloid-beta peptide (Aβ), intracellular Neurofibrillary Tangles
(NFTs) composed of paired helical filaments of hyperphosphorylated tau protein and marked
neuroinflammation. Two main proteins take play a major role in the pathogenesis of AD: Aβ
and tau. Two primary hypotheses -amyloid cascade hypothesis and tau hypothesis- have
been put forward on the basis of the various causative factors in order to explain which
protein aggregate plays a more primal role in AD pathogenesis. Therefore two different lines
of thought have evolved, one proposing that AD starts with the accumulation of Aβ and the
other suggesting that AD starts with the accumulation of p-tau.

Amyloid Cascade Hypothesis

The amyloid-cascade hypothesis was first described in 1992 by Hardy and Higgins [1].
According to this hypothesis, Aβ and its aggregates trigger a cascade harming synapses and
neurons which are responsible for the formation of pathological Aβ plaques, neurofibrillary

23
tangles, synaptic loss, neurodegeneration and ultimately dementia in AD. Aβ peptides are
natural products of brain metabolism, but the balance between production and clearance of
Aβ is disrupted in AD. Aβ is generated by proteolytic cleavage of Amyloid Precursor Protein
(APP) which is synthesized in ribosomes on endoplasmic reticulum and then transported
to the golgi apparatus. APP is a transmembrane protein. It contains an Aβ-encoding region
which is cleaved by a series of secretases: α then γ, or β then γ [2]. Proteolytic processing of
APP occurs by one of two pathways, the non-amyloidogenic or the amyloidogenic (Figure 1).

Non-amyloidogenic Amyloidogenic
pathway Pathway
APP
α- S ecret ase β - S e c re t ase

sAPP-α + C83 sAPP-β + C99

γ-S ecreta s e γ-Secretase

P3 Aβ

A β aggregation

Neuronal death

Figure 1: Processing of beta amyloid precursor protein.

For non-amyloidogenic cleavage of APP, α-secretase cleaves within the Aβ encoding

region, releasing a soluble fragment, sAPPα, into the extracellular space. After this first
cleavage the remaining C-terminal fragment which includes 83 amino acid residues (C-83)
is subsequently cleaved by γ-secretase within the transmembrane region, generating p3
(Aβ17-40) and APP intracellular domain (AICD). AICD and p3 (3 kDa) peptide are released
into the cytosol and extracellular space, respectively. AICD can potentially translocate to
the nucleus and function as a transcription factor [3]. Aβ species are formed by cleavage
with β- and then γ-secretases of APP in the amyloidogenic pathway. β-secretases include
β-site APP-cleaving enzyme 1 (BACE1) and 2 (BACE2). Cleavage by β-secretases releases a
soluble N-terminus fragment, APPβ (sAPPβ), into the extracellular space and the remaining
C-terminal fragment of 99 amino acid residues (C-99) is still membrane bound. C99 is
further processed by γ- secretase at the C-terminal region of the Aβ sequence, generating
AICD and an insoluble fragment, Aβ, which contains 38–43 amino acid residues. Aβ is
released into the extracellular space where it accumulates and contributes to amyloid
plaque formation [4]. Particularly Aβ42 is more predominant toxic form of Aβ species found
in plaques due to its high hydrophobicity, aggregation and fibrillarization potential [2]. It
readily forms insoluble aggregates. Aβ accumulation in the brain induces oxidative stress
and inflammatory response thus leads to neurotoxicity which contributes to impairment of
cognitive functions.
The balance between different secretase activities is very important in the maintenance of
the physiologic Aβ levels. It has been thought that increased production of Aβ and/or decreased
degradation by Aβ-degrading enzymes, or reduced clearance across the blood-brain barrier
may cause aggregation and accumulation of Aβ in the brain. Proteolytic degradation by the
proteases, neprilysin and Insulin Degrading Enzyme (IDE), uptake by astrocytes and microglia
and passive flow into the cerebrospinal fluid and sequestration into the vascular compartment
by soluble form of the low-density Lipoprotein Receptor Related Protein 1 (LRP1) are the major
pathways to remove Aβ peptides from the brain [5,6]. The degradation and clearance of Aβ from
the brain have been suggested to be impaired in patients with AD [7,8]. Aβ aggregates may lead
to a cascade of pathological events ranging from excitotoxicity, endoplasmic reticulum stress,

24
oxidative stress, synaptic dysfunction, mitochondrial dysfunction, loss of calcium homeostasis
and inflammation. However, amyloid-cascade hypothesis alone is not sufficient to explain AD
pathogenesis as removal of Aβ did not halt AD pathology [9].
Tau Hypothesis
Tau is an intracellular protein. It belongs to a family of microtubule-associated proteins that
promotes microtubule assembly and stabilization. Stabilization of microtubules is essential
for normal configuration of neuronal extensions, polarization of cells and also for axonal
transport. Tau has neurotoxic effects when hyperphosphorylated due to loss of its normal
function. Hyperphosphorylation impairs its ability to bind and stabilize microtubules, and
hyperphosphorylated tau has an increased tendency of self-aggregation forming insoluble
fibrils. Hyperphosphorylation of tau promotes the formation of paired helical filaments
which would eventually evolved into NFTs, dystrophic neurites, and neuropil threads [10].
Abnormal hyperphosphorylation of tau is the key player of AD neurodegeneration as the
major component of neurofibrillary tangles in AD. Abnormally hyperphosphorylated tau has
been isolated from AD brain in 1990s [11].
In vitro studies have shown that tau phosphorylation at different sites may cause
different effects in its biological function as well in pathogenic role. Phosphorylation of tau
at Ser262, Thr231, and Ser235 has been shown to inhibit its binding to microtubules by
∼35%, ∼25%, and ∼10%, respectively [12]. Phosphorylation of tau is catalyzed by enzymes
known as protein kinases. An inappropriate activation of tau kinases such as glycogen
synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk-5) and c-Abl has been thought
to cause of tau hyperphosphorylation and subsequent NFT formation [13].
A sizeable body of evidence has demonstrated that tau has additional roles including regulation
of synaptic function and neuronal signaling which may be involved in AD pathogenesis. Tau
has been thought to play an important role in regulation of synaptic function by interacting
with synaptic proteins (e.g post synaptic density protein PSD-95) which is involved in regulation
of synaptic plasticity. The abnormal tau phosphorylation has been suggested to distrupt the
interaction between tau and -95/NMDA receptor complex [14].
Tau protein may also be involved in regulation of mitochondrial dynamics. Abnormal
phosphorylation of tau may directly influence mitochondrial function by decreasing ATP
production and increasing susceptibility to oxidative stress [15]. The mislocalization and
accumulation of tau proteins in dentrites and dentritic spines may distrupt neuronal cell
communication which leads to neurodegeneration and loss of memory [16].
Although both hypotheses suggest primal roles of Aβ and tau protein in AD pathogenesis,
increasing evidence suggests that there may be a crosstalk between two pathologies. Aβ can
facilitate NFT formation [2] and tau pathology can affect the formation of amyloid plaques [17].
Aβ interacts with tau pathology via three pathways leading to tau hyperphosphorylation and
tau axonal transport deficits which result in NFT formation (i) Aβ activates tau kinase, GSK-
3β, and induces GSK-3β-mediated phosphorylation of the Kinesin Light Chain (KLC) leading
to altered deposition of tau and subsequent NFT formation, (ii) Aβ may induce proteasome
dysfunction leading to decreased tau degradation and increased tau aggregation, (iii) Aβ
activates caspase-3 which is responsible for tau truncation and tau aggregation [18]. On
the other hand, tau-related pathways affect APP processing and Aβ formation. Tau kinases
may phosphorylate APP and activate γ-secretase leading to formation and aggregation of Aβ
oligomers. In addition, APP axonal transport deficits and altered APP production may occur
depending on the inhibition of tau degradation [19]. However, the mechanisms linking Aβ
toxicity and tau hyperphosphorylation have not been exactly clarified yet.

Pathogenic Mechanisms in Alzheimer’s Disease

Oxidative Stress
Oxygen metabolism generates free radicals such as Reactive Nitrogen Species (RNS)

25
and Reactive Oxygen Species (ROS) including superoxide anion and hydroxyl radical. Free
radicals have unpaired electrons in separate orbitals in theirs outer shell and exhibit a
high reactivity. They readily interfere with biomolecules such as lipids, proteins and nucleic
acids in organelles and subsequently alter their structure and function. Free radicals
produced by oxygen metabolism play important role in cell signaling and homeostasis.
However, an imbalance between their production and clearance from the body results in
oxidative stress. Environmental factors such as UV, ionizing radiation, certain drugs and
chemicals can enhance free radical production causing oxidative stress. Oxidative stress on
polyunsaturated membrane lipids results in alteration of the membrane properties such as
fluidity, ion transport, enzyme activities and eventually leads to cell death. Protein oxidation
causes to impaired cellular metabolism whereas DNA oxidation leads to formation of DNA
strand breaks and mutation. Transition metal ions such as iron and cupper promote free
radical production due to their pro-oxidant property. In the presence of these metal ions,
free radical production increases via Fenton and Haber-Weiss reactions. Harmful effects of
free radicals can be prevented by antioxidant defence system that contains small antioxidant
molecules and antioxidant enzymes such as Superoxide Dismutase (SOD), Catalase (CAT),
glutathione peroxidase and glutathione reductase. Impaired antioxidant defence is the most
important factor for development of oxidative stress.
Increased oxidative damage is an early change in AD patients. The levels of protein
carbonyls and 3-nitrotyrosine (protein oxidation markers), 8-hydroxydeoxyguanosine (8-
OHdG) and 8-hydroxyguanosine (DNA and RNA oxidation markers), malondialdehyde (MDA),
4-hydroxynonenal, and F2-isoprostanes (lipid peroxidation markers) have been found to be
elevated in AD brains [20,21]. Increased oxidative stress in AD is attributed the pro-oxidant
role of Aβ. Aβ possesses pro-oxidant properties that can influence oxidative processes. At
high micromolar and nanomolar concentrations, Aβ aggregates form fibrils and induce free
radical formation, lipid and protein oxidation, DNA damage and subsequently cause neuronal
death. Transition metal ions including iron and copper are required for pro-oxidant activity
of Aβ. Direct interaction between Aβ and transition metal ions may result in increased free
radical formation [22]. Aβ treatment has been shown to increase the levels of hydrogen
peroxide and lipid peroxides in both cell and animal models [23,24]. On the other hand,
as a closed circuit, oxidative stress also promotes Aβ production by decreasing α-secretase
activity while promoting β- and γ-secretase expression and activity [25]. Although data is
highly limited, oxidative stress may also influence hyperphosphorylation and polymerization
of tau protein. It has been suggested that the elevated amounts of fatty acid oxidation that is
determined in AD patients, can facilitate the polymerization of tau [26].Antioxidant defence
capacity is the main determinant in development of oxidative stress. Neurons are vulnerable
to free radical attacks since their glutathione content, a powerful antioxidant, is relatively
low and their membranes contain a high amount of polyunsaturated fatty acids. Defective
antioxidant defense, increased oxidative stress and enhanced Aβ deposition have been
shown in APP overexpressing transgenic mice [27]. Dumont et al. have demonstrated that
facilitation of the mitochondrial antioxidant defence improves resistance to Aβ, decreases
plaque formation or increases plaque degradation in a transgenic AD mouse model [28].
Recently, the possible role of SOD in AD pathogenesis has been demonstrated in Tg2576
APP-overexpressing AD mouse model. In this model a cytoplasmic copper/zinc superoxide
dismutase deletion has been found to be associated with increased Aβ oligomerization,
accelerated loss of memory and spatial learning [29]. On the other hand, aging is a natural
and inevitable process and is associated with a prolonged free radical production. Due to
the decline in antioxidant defence capacity during aging, human body is insufficient to
counteract the free radicals. Since AD is generally seen in elderly individuals, increased
oxidative stress in AD patients may be partially attributed to advanced age. As a matter of
fact, activity of antioxidant enzymes including SOD, catalase, glutathione peroxidase and
glutathione reductase have been reported to be decreased in brains of patients with AD [30].
Inflammation is a free radical-producing state. Neuroinflammation is a contributory factor

26
in AD pathogenesis that will be described below. Production of free radicals by glial cells
due to inflammation may exacerbate the oxidative stress in AD patients.Taken together,
oxidative stress is a key player in AD but it is still contraversial whether it plays a causative
role in the disease or secondary to the pathological changes seen in AD.
Neuroinflammation
Neuroinflammation is a process including activation of innate immunity in the brain.
Neuroinflammation functions in protecting central nervous system from infectious insults,
injury or diseases. Microglia is key players in neuroinflammation. Neuroinflammation is an
early event in the pathogenesis of AD. Transgenic animal models of AD have demonstrated
that neuroinflammation is enhanced around amyloid plaques [31]. Microglial activation have
dual effects on AD progression: (i) activation of microglia results in production of cytokines
and chemokines which in turn initiate phagocytic activity and thus help Aβ clearence and
degradation [31], (ii) prolonged microglia activation initiates a pro-inflammatory cascade
and disease proceeds to chronic state that synaptic dysfunction, mitochondrial damage,
further activation of microglia, and eventually neuronal death occur [32].
Microglial activation results in production and release of pro-inflammatory cytokines
such as interleukin IL-1β, IL-6, IL-8, tumor necrosis factor-α (TNF-α), chemokines, ROS
and RNS that lead neuronal and vascular degeneration in AD brains [33]. In addition,
these cytokines stimulate the nearby astrocyte–neuron to produce further amounts of Aβ42
[34]. Not only synthesis of pro-inflammatory cytokines but also their cognate reseptors
are upregulated in AD patients [35]. In vitro studies have demonstrated that blood- brain
barrier is disrupted in AD. Blood–brain barrier dysfunction has been attributed to (i) Aβ42
that is able to modify the expression of tight junction proteins and alter barrier properties
[36], (ii) pro-inflammatory cytokines that cause the loss of tight juctions and breaching the
blood–brain barrier [37].
Oxidative stress is a driving force for neuroinflammation. Free radicals in the term of
ROS and RNS can mediate redox signaling leading to activation of transcription factors
which control the expression of pro-inflammatory cytokines, chemokines and other ROS/
RNS- generating enzymes. As a closed circuit, ROS and RNS production increase due to
neuroinflammation. The link between neuroinflammation and Aβ deposition is BACE1 that
is involved in amyloidogenic processing of APP. BACE1 gene expression is controlled by
NF-κB signaling that is activated by inflammation [38]. BACE1 expression is upregulated
upon inflammatory stimuli leading to increased production of Aβ [39]. On the other hand,
Aβ induces the expression of inflammatory cytokines and enzymes by stimulating NF-κB
and MAPK signaling pathways. As a closed circuit, Aβ accumulation in senile plaques
may produce sequential inflammatory events and excitotoxicity which in turn cause
neurodegeneration and cognitive impairment [40].
Bellucci et al., [41] have suggested that inflammation may play a significant role in the
events leading to neurodegeneration in the tauopathies. They have found that production of pro-
inflammatory cytokines (IL-1β) and enzymes (COX-2) are increased in tau-positive nerve cells in
brainstem and spinal cord. According to these findings NFTs may trigger neuroinflammation by
activating microglia. It has been shown that suppression of neuroinflammation is concordant
with reduction in Aβ plaques and hyperphosphorylated tau in brain, and is associated with
improvements in cognitive and behavioral deficts in AD mouse models [42-44]. Treatment
with antitumor necrosis factor-α (anti-TNF-α) or interleukin-1β (IL-1β) antibodies is efficient in
reducing the pathology in animal models of AD [45,46]. Nonsteroidal anti-inflammatory drugs
[NSAIDs ) and peroxisome proliferator-activated receptor-γ [PPAR-γ) agonists have been shown
to reduce the expression and activity of β-secretase and lower Aβ secretion [47]. Suppression of
neuroinflammation with NSAIDs has been suggested to rescue memory and cognitive decline.
However, retrospective epidemiological studies have demonstrated that prolonged treatment
with NSAIDs delays onset of AD when initiated early stage or before disease initiation [48], but
its efficiency has not been shown in neither mild nor moderate forms of AD [49].

27
Metal Toxicity
Trace elements such as iron, zinc and copper are crucial for neuronal function. However
these metal ions accumulate in brain during the aging and contribute to neurodegeneration.
Metal homeostasis is disrupted in AD brain. Zinc, copper and iron have been found to be
accumulated within the core and periphery of senile plaques and these metals have been
suggested to be involved in Aβ aggregation and oxidative damage [50]. In the presence of Fe2+
or Cu2+, hydrogen peroxide yield the hydroxyl radical via Fenton and Haber-Weiss reactions.
Therefore iron and copper accumulation lead to an increase in oxidative stress.
Aβ contributes to oxidative stress indirectly by damaging mitochondria and directly
by regulating the redox activity of several metals such as iron and copper [51]. APP and
its Aβ fragments have specific binding sites for Cu2+ and Fe3+ions [52]. In vitro studies
have demonstrated that Aβ-copper complexes catalytically produce hydrogen peroxide and
hydroxyl radical and eventually induce oxidative damage [53]. There is growing evidence
that copper can facilitate Aβ aggregation by binding to Aβ which results in Aβ plaque
burden [54]. On the other hand, there is evidence that APP has potential benefical effect
on reducing ROS generation. APP contains an Iron Responsive Element (IRE) on the 5’
untranslated region of its mRNA [55]. APP translation is thus responsive to cytoplasmic free
iron levels. When cellular iron levels are high, translation of APP is increased. Ferroxidases
prevent oxidative stress caused by Fenton and Haber-Weiss reactions by oxidizing Fe2+ to
Fe3+. APP possesses ferroxidase activity which is demonstrated in primary neuron cultures.
It catalytically oxidizes Fe2+, loads Fe3+ into transferrin which in turn causes to neuronal
iron export and a decrease in ROS production. Due to its ferroxidase activity APP may be
upregulated in response to increased iron stores in AD brain [56].
Zinc may accelerate the precipitation of Aβ and produce protease-resistant “non-
structured” aggregates [57]. It has been suggested that compounds affecting zinc homeostasis
can decrease Aβ deposition in the brain [58]. Deregulation of neuronal Zn2+ homeostasisis is
believed to be strictly connected to oxidative stress. Zn2+ can trigger free radical production
by interfering with the activity of the electron transport chain (inhibits complex I and III)
[59]. In addition, Zn2+ may contribute to iron accumulation and free radical production by
inhibiting the ferroxidase activity of APP [56]. On the other hand, zinc and iron promote tau
phosphorylation and aggregation by binding to tau [60].
Aluminium (Al) is a known neurotoxin which may have various adverse effects on central
nervous system. Al can access to the brain via blood-brain barrier and it accumulates in
a region-specific manner. There is some evidence, although it is controversial, that Al may
trigger all major histopathological events associated with AD. Independent studies have
shown that Al strongly promotes amyloid aggregation and accumulation at physiologically
concentrations [61,62]. After chronic oral exposure, Al elevates APP expression, promotes
Aβ deposition and amyloidosis in hippocampal and cortical pyrimidal neurons in rats and
mice [63,64]. Al binds the amyloidogenic Aβ peptide resulting in the formation of neurotoxic
Aβ-sheet conformation [65]. While the role of Al on tau-related pathology has been shown
in vitro, in vivo studies are limited. Al catalyzes a covalent transfer of entire triphosphate
from ATP to tau in vitro. Therefore it promotes the phosphorylation of tau non-enzymatically
[66]. It may cause neurofibrillary abnormalities, synaptic loss and distrupt axonal
transport mechanisms. It has been reported that Al-induced NFTs are made up of normal
neurofilaments instead of abnormal tau proteins [67]. Al may affect neuroinflammatory
signaling by promoting NF-κB expression which is upregulated in AD [68]. In addition, Al
may contribute to AD via causing oxidative damage to neurons through Fe [69]. Al stabilizes
ferrous (Fe2+) ion which catalyzes the Fenton reaction, thus leads the enhanced oxidative
damage that may exacerbate events associated with AD. Metal chelation therapy based on

28
binding and removing to these metal ions can provide a beneficial effect against oxidative
stress in AD. Treatment with metal chelators such as clioquinol and desferrioxamine have
provided some success in altering the progression of AD [70,71]. Therapeutic approaches
targeted to restore metal balance are an active area of current investigations in the field of
AD.
Mitochondrial Dysfunction
Hypometabolism is a hallmark of AD. Mitochondrial dysfunction plays important
role in both brain aging and AD. For the first time, Swerdlow and Kan have proposed
mitochondrial cascade hypothesis for sporadic form of AD in 2004 [72]. According to this
hypothesis, mitochondrial dysfunction occurs early in disease pathogenesis and causes Aβ
deposition, synaptic loss and NFT formation that are seen in AD [73]. The mitochondria is
the major source of ROS in the central nervous system, and is also particularly vulnerable
to oxidative stress due to lack of DNA repair activity. Oxidation of mitochondrial DNA
renders it vulnarable to somatic mutations which augments mitochondrial dysfunction. In
addition to ATP production, mitochondria carry out significant cellular processes including
maintainence of Ca+2 homeostasis, regulation of cellular metabolism and apoptosis [74].
Impaired Ca2+ homeostasis leads to excessive Ca2+ uptake into mitochondria which in turn
initiates apoptosis [73]. Mitochondrial dysfunction has been suggested to trigger onset of
neuronal degeneration in AD. Mitochondrial abnormalities in their number and size, deficient
energy production, increased mitochondrial degradation by autophagy, decreased cytocrome
oxidase (complex IV) activity, and a decrease in activity of certain tricarboxylic acid cycle enzymes
(especially pyruvate dehidrogenase and α-ketoglutarate dehidrogenase ) have been determined
in AD brains [75,76]. Mutations in mitochondrial DNA arising from impaired mitochondrial
bioenergetic have been detected in AD patients. These mutations are associated with
decreased cytochrome oxidase activity. It has been suggested that since decreased cytochrome
oxidase activity is accompanied by the decline in mitochondrial respiratory function, it eventually
proceeds to neuronal damage and cognitive decline in AD [77].
Aβ has been shown to accumulate in mitochondria from AD patients. Intracellular and
mitochondrial accumulation of Aβ likely precedes extracellular Aβ deposition. Aβ deposits
can increase mitochondrial damage directly and indirectly. In direct manner, Aβ deposits can
disrupt lipid polarity and protein mobility in mitochondrial membranes, break membrane
potential, inhibit key enzymes of the mitochondrial respiratory chain and decrease ATP
production [78,79]. The indirect effect of Aβ deposits on mitochondrial dysfunction occurs in
synaps. Synaptic loss is one of the major characteristics of AD. In neurons mitochondria are
significantly more likely to be localized at synapses and are essential for the formation and
maintenance of synapses. Abnormalities in mitochondrial functions contribute to synaptic
dysfunction and eventually synaptic loss.
After the synthesis, APP is targeted to both mitochondria and plasma membrane by virtue of
N-terminal chimeric signals. Aβ is transported into the mitochondria by mitochondrial import
channels. APP has been shown to accumulate exclusively in the protein import channels of
mitochondria of human AD brains but not in age-matched controls. It has been determined
that decreased function of mitochondrial import channels due to the overproduction of APP
leads to decreased translocation of nuclear-encoded cytochrome c oxidase subunits IV and
V proteins that are essential for mitochondrial function [80].
Tau protein may also be involved in mitochondrial dysfunction in synaps, indirectly. There
are several studies indicating that hyperphosphorylated tau may contribute to worsening of
AD progression by effecting complex I, mitochondrial transport and mitochondrial dynamics
[81]. Tau can bind kinesin, a motor protein which transports mitochondria along axons

29
to synapses with other transport proteins. Under conditions of elevated tau, transport of
mitochondria along axons to synapses is impaired. Phosphorylated tau prevents transport
proteins to attach which results in improper synaptic activity and synaptic degeneration
[82, 83].
Brain Insulin Resistance and Insulin Deficiency
Type 2 diabetes mellitus is a risk factor for AD, and AD risk is increased in patients
with type 2 diabetes. AD and type2 diabetes share many common pathological processes.
The features of both disorders are influenced by abnormal systemic and/or brain glucose
metabolism and insulin signaling pathways. Impaired glucose metabolism is associated
with increased oxidative stress and accumulated advanced glycation end products that both
create a viscious cycle involving oxidative stress and mitochondrial dysfunction.
Pancreatic insulin is transported by cerebrospinal fluid into the brain and crosses the
blood–brain barrier by an active and saturable process [84]. Insulin is even produced in
brain tissue itself [85]. Insulin receptors are mostly located in the cerebral cortex, olfactory
bulb, hippocampus, cerebellum, and hypothalamus where are the cognition pertinent areas
of the brain. They are largely localized in neurons, being less abundant in glia. Insulin
can also bind to insulin like-growth factor 1 (IGF-1) receptors on the neurons. By binding
neuronal insulin and/or IGF-1receptors, insulin regulates physiological functions such
as food intake, inhibition of hepatic gluconeogenesis, counter-regulation of hypoglycemia,
reproduction, modulation of tau protein phosphorylation, APP metabolism, Aβ clearance,
neuronal survival, neurotransmission, learning and memory [84,86]. In addition, insulin
acts as a growth factor for neurons. It promotes neurite outgrowth and axonal regeneration.
Insulin also functions by controlling neurotransmitter release processes at the synapses
and activating signaling pathways associated with learning and long-term memory.
Concordantly, defective insulin signalling in the brain has been demonstrated to be an
important factor contributing AD pathology [87]. Recent studies have demonstrated that
brain glucose utilization and insulin signalling are impaired in AD. AD is associated with
a decrease in the levels of insulin in the cerebrospinal fluid, in the ratio of cerebrospinal
fluid insulin/plasma insulin, a decline in the expression of insulin receptors and an
increase in fasting plasma insulin levels [85,88]. Impaired insulin signalling in the AD
brain is attributed to increased oxidative stress. Oxidation of membrane receptors, signaling
proteins, transcription factors, and epigenetic regulators may lead disrupted insulin
signalling and glucose utilization. Impaired insulin signaling may affect AD pathogenesis via
tau hyperphosphorylation, Aβ metabolism and acetylcholine signalling. Decreased insulin
function leads to the over-activation of GSK3β, which results in hyperphosphorylation of
tau, followed by formation of NFTs [89,90]. Insulin and IGF-1 signaling have beneficial effects
on Aβ homeostasis. They promote tissue clearance of Aβ and non-amyloidogenic pathway
of APP processing; consequently protect neurons from Aβ toxicity [91]. On the other hand,
insulin stimulates the expression of choline acetyltransferase, the enzyme responsible for
acetylcholine synthesis. Therefore, decreased insulin levels as well as insulin resistance can
ultimately contribute to a decrease in acetylcholine in AD brains [92].

Genetic Aspect of AD
Generally, AD is classified as familial and sporadic. Late-onset sporadic form constitutes
the vast majority of AD cases (95 % of cases). Autosomal dominant early-onset familial
form represents only about a small fraction of all AD cases (5% of cases) but progresses
much faster than sporadic form of AD. Familial form of AD is associated with mutations
in genes encoding APP on chromosome 21, and the subunits of the APP cleaving enzyme,
γ-Secretase, Termed Presenilin-1 (PSEN-1), on chromosome 14 and presenilin-2 (PSEN-2) on
chromosome 1 [93,94]. Although missense mutations in the APP gene are first to be identified
in familial AD, they only account for a small fraction (~0.1%) of all familial AD mutations

30
[95]. Mutations in PSEN-1 and PSEN-2 are account for the vast majority of familial AD
mutations with over 150 currently identified mutations [96]. PSEN-1 and PSEN-2 mutations
are associated with changes in APP processing that favor overproduction of toxic Aβ42 or an
increase in the proportion of Aβ1-42 to Aβ1-40 (it is generally believed that Aβ1-40 peptides are
non-amyloidogenic while Aβ1-42 are amyloidogenic). Although the exact causes of sporadic
AD are not yet determined, multiple genes and acquired mutations due to environmental
factors (aging, diet, smoking) may increase an individual’s susceptibility or predisposition
to AD. Genome-wide association studies have led to discovery of susceptibility genes that
may be involved in AD pathogenesis. These genes are APOE, bridging integrator 1 (BIN1),
clusterin (CLU), ABCA7 (ATP-binding cassette transporter), Complement Receptor 1 (CR1),
Phosphatidyl Inositol-Binding Clathrin Assembly Protein (PICALM), Membrane Spanning
4-Domains Subfamily (MS4A6A), CD33, MS4A4E and CD2-Associated Protein (CD2AP) [97].
Among these genes, the gene encoding APOE on chromosome 19 contributes the greatest
risk. APOE in humans consists of three major isoforms-APOε2, APOε3, and APOε4- which
are encoded by different alleles (epsilon [ε] 2, 3, and 4). APOE is synthesized and secreted
mainly by astrocytes. Its main function is lipid transport in the brain. In addition, APOE
plays important role in regulation of brain Aβ peptide levels by binding Aβ peptides and
facilitating their proteolytic degradation. Aβ peptides are proteolytically degraded within the
brain by neprilysin and insulin degrading enzyme. The degradation of Aβ peptides within
microglia by neprilysin and extracellulary Aβ degradation by insulin-degrading enzyme are
facilitated by APOE. It has been suggested that Aβ clearance with the Apoε4 isoform is less
effective than other isoforms in facilitating degradation of these peptides [98]. Although the
APOε4 allele is represented in approximately %25 of population, it has been postulated to
be a risk factor for sporadic AD in older adulthood [99]. Cross-sectional studies in patients
with AD have shown that the APOε4 allele is associated with impaired memory function,
more severe atrophic changes and hypometabolism in the medial temporal lobe structures
[100-102]. Autopsy studies on AD have indicated the APOε4 allele to be associated with
greater densites of Aβ deposition, senile plaques and neurofibrillary tangles, especially in
the hippocampus [103]. Besides this, the APOε2 allele may have a protective effect against
AD. APOε2 carriers are associated with less Aβ plaques and neurofibrillary tangles than
both APOε4 carriers and APOε3 homozygotes [104]. However, the influence of APOε4-allele
on development, progression, clinical presentation of AD and rate of cognitive decline have
not been fully described yet.
BIN1 has been suggested to be the second most important risk locus which is responsible
for late onset AD. BIN1 is a member of the (BAR) family of genes that are involved in various
cellular processes, including endocytosis, actin dynamics and membrane trafficking/
tubulation. A BIN1 variant (rs59335482; an insertion of three C bases) which is associated
with increased AD risk has been identified in three independent AD case–control cohorts.
Insertion has found to led overexpression of BIN1 in cell cultures [105]. Although BIN1
is related with calcium homeostasis, inflammation and apoptosis, it is likely involved in
AD pathogenesis by modulating tau pathology. It has been reported that knocking down
the BIN1 significantly suppresses tau-derived neurotoxicity [105]. The BIN1 expression has
been reported to be increased at onset and in shorter disease duration in AD patients [106].
CLU is a multifunctional glycoprotein that is also termed as apolipoprotein J. It is
involved in regulation of brain lipid metabolism, prevention of inflammation and reduction
of oxidative stress and apoptosis. It prevents fibril formation by binding Aβ peptides and
faciliating their transport into the bloodstream. CLU concentration in peripheral blood has
been found to be clearly increased in AD. However, it is still need to be clarified how CLU
variants influence the development of AD [107,108].

31
 Another susceptibility gene for sporadic AD risk is ABCA7. Gene product, ABCA7, is
a member of the ATP-binding cassette superfamily of transporters. It is a multispan
transmembrane protein, and is most abundantly expressed in the microglial cells in the
brain. ABCA7 may contribute to the pathophysiology of AD via various pathways including
Aβ accumulation, lipid metabolism and phagocytosis. The levels of ABCA7 have been found
to be increased in the AD brain, and are positively correlated with amyloid plaque burden
and disease severity. Several studies have identified different SNPs in ABCA7 related to
sporadic AD [109].
Complement signaling pathways which are required for proper microglial function may
be altered in AD, leading to reduced ability to phagocytose apoptotic cells and clear Aβ.
CR1 is involved in the clearance of amyloid plaques. Genetic variations in CR1 have been
reported to be associated with global cognitive decline, higher burden of AD brain pathology
and increased risk for AD [110, 111]. In summary, many susceptibility genes have been
suggested to be associated with sporadic AD risk [112]. Although the association between
sporadic AD risk and some genes has been confirmed by several recent genome wide
association studies, genetic case-control studies and meta-analyses which provide better
understanding on their precise roles in sporadic AD are still far from complete.

Epigenetic Aspect of AD
Epigenetic mechanisms are defined as acquired and heritable modifications on DNA
that regulate the gene expression without affecting the DNA base sequence. They act on
genes through reversible changes leading to their activation, repression or silencing. Thus,
epigenetically regulated or dysregulated transcription states can cause to development
of healthy or pathological states. Epigenetic modifications are classified in three types:
DNA methylation, histone modifications and non-coding RNAs. Epigenetic modifications
are dynamic and unlike genetic mutations, they can be reversed by environmental factors
and therapeutics. Physical and behavioral factors, nutrition, physical and mental exercise,
environmental pollutants, pesticides, chemicals and certain metal ions affect the epigenetic
mechanisms. Especially, nutrition is one of the main epigenetic regulators. Folate, vitamin
B12, beta in, choline and methionine play a pivotal role in DNA methylation as well in
maintenance of genomic stability. In addition to their antioxidant properties, dietary
polyphenols modify epigenetic mechanisms.
There is an overwhelming scientific consensus that epigenetic changes contribute to
aging and aging-associated diseases. Genetic mutations are involved in the pathogenesis of
familial AD, but epigenetic mechanisms are likely to be important in the etiology of sporadic
form of AD. Epigenetic mechanisms involved in the AD pathology has become increasingly
clear with novel researchs. Recently, the diet containing nutrients that are able to modify
epigenetic mechanisms has been suggested as a preventive approach for AD [113].

Aberrant DNA methylation in AD

DNA methylation is the most widely studied epigenetic mechanism. DNA
methyltransferases ( DNMT1, DNMT2, DNMT3A and DNMT3B) catalyze the transfer of a
methyl group to the carbon atom in position 5 of a cytosine moiety in the presence of
the methyl donor S-adenosyl methionine (SAM). DNA methylation occurs at the CpG rich
regions, called CpG islands, in gene promoters. Methylation at this site disrupts the binding
of transcription factors and repress the transcription. Therefore, hypermethylation results
in gene silencing whereas hypomethylation is associated with active chromatin Vitamin
B12, B6 and folic acid influence DNA methylation patterns altering SAM availability via
metabolites of the SAM cycle (Figure 2).

32
 DHF Folate

Homocysteine THF

B6
SAH
dimethylgltcine
Methionine 5, 10-
Synthase methylene THF
Choline
B1Z
SAM
Betain B2
CH3
Methionine 5-methyl THF

DNA methylation
Figure 2: S-Adenosyl Methionine Cycle.

SAH:S-adenosylhomocysteine, SAM: S-adenosylmethionine, THF: tetrahydrofolate, DHF:

dihydrofolate
Numerous studies have shown that there is a consistent decrease in global DNA
methylation in both normal aging and AD [114,115]. Aberrant DNA methylation profiles
have been detected in AD patients even if they are in the preclinical stage [116]. Although
AD is associated with global DNA hypomethylation in middle frontal gyrus and middle
temporal gyrus [117], specific gene regions and loci such as APP, PSEN1 have been reported
to be hypo- or hypermethylated. An enormous research effort has been directed towards to
understanding the causative role of DNA methylation status of AD-related gene promoters
in the pathogenesis of disease. However findings of different studies are inconsistent and
the role of DNA methylation in AD pathogenesis still remains unexplained. For example,
hypomethylation-associated overexpression of the APP gene has been demonstrated in the
brain of an Alzheimer’s patient [118]. However in another study, no significant difference
has been found in the methylation level of APP gene in AD patients as compared with
controls [119]. There is evidence that Aβ can modulate DNA methylation. In murine cerebral
endothelial cell cultures Aβ1–40 treatment has been shown to reduce the status of global DNA
methylation whereas increase the DNA methylation on the promoter region of neprilysin
that is an enzyme involved in Aβ degradation [120]. DNA methylation change in promoter
of PSEN-1 gene has been examined in AD. According to data of human postmortem brain
tissue studies, PSEN-1 gene promoter has a very low level of methylation and reduced
DNA methylation is associated with increased PSEN-1 gene expression [121,122]. However,
most recently, the methylation status of PSEN-1, BACE1, DNMT1, DNMT3A and DNMT3B
promoters in blood DNA obtained from AD patients and controls have been analysed and
it has been reported that none of the studied regions is differently methylated between AD
and controls [123]. Some other genes that are thought to be involved in AD pathogenesis
have also been investigated in respect with the promoter methylation status. The promoters
for cAMP-responsive element that is associated with synaptic plasticity have been found to
be hypermethylated in AD [124]. GSK3β is the major kinase that phophorylates tau protein
in the brain. It has been reported that GSK3β activity and expression levels are increased
in AD brains which may be due to hypomethylation of its promoter region [125]. Promoter
methylation of Neuronal protein phospatase 2A has been found to be downregulated in affected
brain regions of AD patients, causing the accumulation of both phosphorylated tau and APP
isoforms, and increased secretion of Aβ peptides [126,127]. Promoters of cyclooxygenase-2,

33
brain-derived neurotrophic factor and NF-κB have been reported to be hypomethylated,
whereas promoters of cAMP resonse element-binding protein and synaptophysin have been
reported to be hypermethylated in the frontal cortex of postmortem AD brain [124].
Taken together, although DNA methylation changes have been determined in AD
brains the causative role of DNA methylation on amyloidopathy and taupathy have not
been fully understand yet. However, it is clear that DNA methylation is strictly linked to
folate/methionine/homocysteine metabolism (see figure 2). An experimental study with
APP-overexpressing transgenic mice fed with a folate/B12/B6-deficient diet has resulted
in increased S-Adenosylhomocysteine (SAH)/SAM ratio, upregulated PSEN-1 and BACE,
and enhanced Aβ accumulation [128]. The lower availability of SAM may be related to the
altered expression of genes involved in APP metabolism and Aβ accumulation. As a matter
of fact, SAM level has been demonstrated to be decreased in post mortem AD brain [129];
plasma homocysteine levels have been found to be increased whereas serum folate levels
are decreased in late-onset AD patients with respect to controls [130]. Therefore, the global
hypomethylation determined in AD brain may be due to abnormal levels of the intermediates
producing through folate/methionine/homocysteine metabolism.
In light of these considerations, it has been concluded that folate, vitamin B12 and
vitamin B6 are not only required for growth and neurotransmitter synthesis but also
essential for maintenance of physiological DNA methylation patterns in the brain. Their
deficiency may result in aberrant DNA methylation profiles which have been detected in AD
patients.

Histone modifications in AD
The reversible post-translational histone modifications and subsequent chromatin
remodeling play important role in regulation of memory and learning. Histone proteins
undergo various post-translational modifications including acetylation, methylation,
phosphorylation, ubiquitination, sumoylation and Adenosine Diphosphate (ADP)-ribosylation.
Among these modifications, acetylation/deacetylation is the most extensively studied type
of histone modification due to its regulating function on gene expression. Acetylation status
of histones is maintained by the opposing actions of Histone Acetyltransferases (HATs)
and Histone Deacetylases (HDACs). HATs catalyze the transfer of an acetyl group from
acetyl-coenzyme A to lysine residues on the N-termini of histone proteins. HDACs remove
acetyl groups from acetylated histone proteins. In general, histone acetylation is linked to
chromatin decompaction and transcriptional activation. In contrast, deacetylation leads to
more condensed chromatin state and transcriptional repression or silencing. HDACs are
classified into four classes as I, II, III and IV according to their sequence homology.
After the discovery of the fact that histone acetylation is associated with cognitive
functions, role of histone modifications in AD has been investigated with experimental
studies. Treatment with HDAC inhibitors have provided some benefits in memory and
learning in transgenic mice models of AD [131]. Su et al., [132] have reported that valproic
acid, a HDAC1 inhibitor, decreases Aβ production and reduces plaque formation in the
brains of APP (V717F) transgenic mice. Also, daily given phenylbutyrate, HDAC inhibitor,
have been reported to reverse spatial memory loss and maintain normal phosphorylated tau
levels in the hippocampus of transgenic Tg2576 mouse model of AD, but it has no effect on
Aβ levels [133].
Sirtuins are NAD+- dependend class III HDACs. Seven sirtuins (SIRT1-7) have been
identified in mammals, with varied roles in chromatin integrity, metabolic regulation,
oxidative stress, DNA repair and apoptosis. In early 2000s, epidemiological studies have
revealed that individuals who maintain a low calorie diet have a reduced risk of developing

34
AD. The influence of calorie restriction on AD pathology has been examined in AD mouse
models, and it has been shown that calorie restriction reduces amyloid plaques by activating
SIRT1 [134,135]. This neuroprotective effect has been attributed to an increase in NAD+
/NADH ratio and subsequent activation of SIRT1during the calorie restriction. SIRT1 is
the most frequently studied HDAC in AD. According to results of studies with cell culture
models and transgenic mouse models, SIRT1 overexpression increases α-secretase activity,
reduces Aβ formation, promotes neuronal survival [136] and inhibits neuroinflammation
[137]. Furthermore SIRT1 deacetylates the acetylated tau and promotes its degredation
and clearance. SIRT1 downregulation has been shown to inhibit tau polyubiquitination and
tau turnover, thus results in accumulation of phospho-tau [138]. It has been reported that
cortical SIRT1 expression is decreased in autopsy specimens of AD patients but not in the
individuals with mild cognitive impairment ; SIRT1 mRNA and protein levels are negatively
correlated with the duration of symptoms and the accumulation of tau, but are weakly
correlated with the Aβ42 [139]. In accordance with these data, a significant decline in serum
SIRT1 level has been determined in patients with both AD and mild cognitive impairment
in comparison to healthy elderly individuals [140].
In light of these data, SIRT1 activation seems as an useful approach to prevent onset
and progression of AD. Resveratrol is a naturally occurring polyphenol found in red grapes
and red wine. It is known with its antioxidant, anti-carcinogenic and anti-inflammatory
activities. In addition to these properties it is a powerful activator of SIRT1 [141]. SIRT1
activation by resveratrol has been shown to protect against amyloid plaque formation in
AD models. Resveratrol is undergoing evaluation in clinical trials (www.clinicaltrials.gov).
SIRT3 regulates mitochondrial energy metabolism and mitochondrial dynamics. SIRT3 has
been thought to be involved in neuroprotection by decreasing ROS production. However the
number of SIRT3 studies is highly limited in the field of AD.
MicroRNAs in AD
miRNAs are small (approximately 22 nucleotide length) non-coding RNAs that play a
significant role in the regulation of gene expression in a post-transcriptional manner. miRNAs
bind specific target mRNAs in the 3’-untranslated region and supress their translation and/
or promote their degradation. More than 30,000 miRNAs have been identified in humans.
miRNAs play an important role in various processes such as proliferation, differentiation and
apoptosis in both healthy and pathological states. miRNAs are highly expressed in different
compartments of the brain and many of them are brain-specific or brain-enriched. miRNAs
have a selective distribution within neurons and synapses. They have been found to regulate
translation of proteins needed for neurite outgrowth, synaptogenesis and activity-driven
synaptic plasticity [142]. They may also control expression of genes related with learning,
memory and cognitive performance in general. Enourmous studies have been conducted to
understand the role of miRNAs in the pathogenesis of neurodegenerative disorders such as
AD [143-145]. Although there are some inconsistent data, several miRNA profiling studies
have independently validated specific miRNAs which are dysregulated in the AD brain
(Table 1). These specific miRNAs may affect the AD-related pathology either directly (by
modulating expression of key genes such as APP and BACE1), or indirectly (by affecting
expression of genes related with neurogenesis and immune response). It has been revealed
that expression of APP gene is modulated by miRNAs and, as a closed circuit, Aβ treatment
also causes to down-regulation of substantial proportion of miRNAs [146]. Therefore Aβ
seems as a powerful regulator of miRNA levels. miRNAs can be used as potential diagnostic
tools due to their stability and convenience of detection in serum. Examination of miRNA
profile may be benefical for early detection of AD (may also be helpful for determination of
AD risk in the first degree relatives of the patients). In addition, modulation of mRNAs may
be a novel therapeutic strategy in AD. However, miRNAs is a relatively novel topic in the
field of AD researches. There are inconsistent findigs probably due to non-homogeneous
experimental conditions. Further studies are needed to better understand miRNA-mediated
gene silencing which contributes to AD pathogenesis.

35
 Affected tissue/expression in AD
miRNA Role in AD pathogenesis Referens
patients
Downregulated in primary neuronal cell
cultures after treatment with Aβ peptides; Upregulated in the hippocampus and
147-149
miR-9 involved in inflammatory and oxidative stress temporal lobe neocortex of AD brains;
pathways in the AD; targets include BACE1, downregulated in the patient serum
SIRT1 and NFκB
Negative correlated with neuritic plaque
miR-107 density; increases BACE1 mRNA levels; Downregulated in AD patients 150-152
targets include BACE1, CDK5 and ADAM10
Involved in the regulation of pro-apoptotic
144, 153, 154
miR-15 markers in AD brain; participates in neuronal Downregulated in AD brains
tau hyperphosphorylation in vivo
Inversely correlated with the density of
Downregulated in human AD temporal
amyloid plaques and BACE1; increases 155, 144
miR-29 cortex,
amyloid production in neuronal cellular
cerebellum and patient serum
models, in vitro
Related with amyloid plaque density, neuritic
Downregulated in temporal cortex of 150, 151, 155
miR-34 plaque counts and neurofibrillary tangle
AD patients
counts; negative corralated with BACE1 level
Downregulated in primary neurons treated
Downreg lated in the AD cortex and 156, 146
miR-181c with exogenous Aβ42 peptides; regulates
cerebrospinal fluid
SIRT1 expression
Directly binds to APP; repress the expression
Downregulated in the temporal cortex
miR-106 of the transporter ABCA1 that results in an 157
of AD brain
increase of Aβ levels
Involved in inflammatory and oxidative stress Upregulated in the temporal cortices
miR-146a 147, 158
pathways as a regulator of AD patients
Upregulated in Down's syndrome, a
Downregulates complement factor H in 159
miR-155 neurological disorder which shows
neurodegenerative brain
AD-like neuropathology with age
Downregulates APP; lentiviral-mediated
overexpression reduces fibrillar Aβ; Indirectly Downregulated in the temporal and 143,144,160, 161
miR-101
contributes to abnormal tau phophorylation; parietal cortex
targets include APP and cyclooxgenase-2
Positive correlated with gray matter
neurofibrillary tangles; upregulated by NF-
κB in response to IL-1β and Aβ42-induced
Upregulated in the hippocampus,
stress in human neuronal glial cell;increased
medial frontal gyrus, cerebellum 156, 147, 148, 158, 159,
miR-125b miR-125b expression disturbs the balance of
and temporal lobe neocortex of AD 162
phosphatase
patients
and kinase activity in cultured neurons;
targets include synapsin II and complementer
factor-H
Reduces expression of APP in human fetal Decreased levels in brain of AD
miR-153 163
brain cultures patients
Downregulates the level of Aβ by inhibiting Decreased levels in cerebrospinal
miR-195 156, 164
the translation of BACE1. fluid of AD patients
Activates neuronal processes and regulates
Decreased expression in
brain -derived neurotrophic factor and methyl 156, 165
miR-132 hippocampus and medial frontal gyrus
CpG binding factor MeCP2 expressions;
of AD patients
accelerates tau hyperphosphorylation

Table 1: miRNAs associated with Alzheimer’s Disease.

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 eBooks

Current and Future Therapeutic Approaches

and Management of Alzheimer ’s disease
Nevra Öksüz1, Murat Güntel2, Prof. Dr. İsmet Melek3 and Prof. Dr. Aynur Özge4*
1
Samandağı Goventment Hospital, Department of Neurology, Hatay,Turkey
2
Elazığ Education ve Research Hospital, Department of Neurology, Elazığ,Turkey
3
Mustafa Kemal University Department of Neurology, Antakya,Hatay
4
Mersin University School of Medicine, Department of Neurology, Mersin,Turkey

Corresponding author: Prof. Dr. Aynur Ozge, Mersin University School of Medicine,
*

Department of Neurology, Mersin/Turkey, Head of the Turkish Alzheimer Society Mersin

Branch, E-mail: aynurozge@gmail.com or aozge@mersin.edu.tr

Abstract
Alzheimer’s Disease [AD] is one of the most challenging threats to the healthcare system
in society. It is believed that this ultimately leads to dysfunction and death of cholinergic
neurons, and compensation for this loss had been the primary focus of first generation
therapeutic agents. The amyloid and tau hypotheses have lead to a focus on amyloid and
tau as therapeutic targets. The current therapeutic goals are to reduce amyloid levels,
prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. There is
also a significant advancement in understanding the function of cholinesterase [ChE] in the
brain and the use of ChE inhibitors in AD. The mechanism of a new generation of acetyl-
and butyryl ChE inhibitors is being studied and tested in human clinical trials for AD. Other
strategies, such as vaccination, anti-inflammatory agents, cholesterol-lowering agents, anti-
oxidants and hormone therapy, are also being studied for treating or slowing the progression
of AD. Although several anti-amyloid β compounds have been examined in clinical trials
as potentially useful drugs, all of them have failed to show significant benefits so far. In
contrast, tau-targeted drugs have been developed and have entered clinical trials. We expect
strongly a therapeutic drug for dementia to be released in the near future. Developments
of early diagnostic tools based on quantitative biochemical markers will be useful to better
follow the course of the disease and to evaluate different therapeutic strategies.

Keywords: Alzheimer Disease; Anti-Amyloid Managements; Cholinesterase Inhibitors;

Disease Modifying Agents; Memantine

Management of Alzheimer’s Disease

The first step in AD management is accurate recognition and diagnosis of the disorder,
and then disclosing that diagnosis in a sensitive and timely way to the patient and others
as appropriate. Disclosure of diagnosis is not harmful, and actually decreases depression
and anxiety in patients and their care-givers [1]. The vast majority of patients with mild
dementia wish to be fully informed and 75% of caregivers wish their relative to be informed

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[2]. Differences among ethnic, cultural, and religious groups may influence how and
what disclosure occurs. It offers the patient opportunity to pursue desired activities and
maximizes individual autonomy and choice by providing information necessary for decision
making and advance planning, including the decision to give informed consent to research
projects and autopsy. At time of diagnosis several issues need to be addressed, including
the provision of high quality understandable information about the illness and its course
to patient and caregiver, a careful assessment for any co-morbidities and consideration
given to other services that may be required including social services, mental stimulation,
occupational therapy, physiotherapy, speech and language therapy.Occupational therapy
can benefit patients daily functioning and reduce the need for informal care [3]. Medico-
legal issues need to be addressed, with driving often needing prompt attention and action
taken according to the legal framework operating in that particular country. Care-giver
support should consist of education about AD, and attending peer support groups may be
helpful. Care-giver stress and depression are common and, if present, more intensive care-
giver support and counselling and/or specific treatment for depression may be needed. The
provision of a standard education and support package to caregivers has been shown in
Randomized Controlled Trials [RCT] to decrease psychiatric symptoms in caregivers and
lead to delays in institutionalisation for patient [4,5]. Management should include clear
arrangements for follow-up, as regular monitoring of medication response and adverse
effects as well as changes in the severity of dementia [using scales like the Mini-Mental
State Examination [MMSE]] should be undertaken. Reassessment for development of co-
morbidity [including carer stress] should be an integral part of management.

Primary Prevention of AD
This refers to the prevention of subsequent dementia in cognitively normal subjects and
is the ultimate goal for AD management. Several risk factors have been well established for
AD, though some [such as age, sex and genotype] are not modifiable. Potentially modifiable
risk factors which have been established through several epidemiological studies include
vascular risk factors [hypertension, smoking, diabetes, atrial fibrillation and obesity] and
head injury while protective factors described include use of antihypertensives, non-
steroidal anti-inflammatories, statins and hormone replacement therapy, high education,
diet, physical activity and engagement in social and intellectual activities. However, whether
modifying these factors will reduce risk of dementia is not yet known. A meta-analysis
concluded that there is no good evidence to recommend statins for reducing the risk of
AD while results of the large, prospective, placebo-controlled Women’s Health Initiative
Memory Study showed that the use of estrogen plus progestin in post-menopausal women
was actually associated with a significantly increased risk of dementia [6,7]. Treatment of
hypertension for prevention of dementia, including AD, has been the best studied risk factor
to date. However, most RCTs have been stopped early because cardiovascular endpoints
were reached, meaning they were underpowered to detect differences in rates of dementia. A
study of treating hypertension in the very old reached similar conclusions, and contained a
meta-analysis of all studies supporting a significant risk reduction [8]. However, the period
over which treatment needs to be given is not known, nor has it been established whether
treating vascular risk factors, including hypertension, in those with established AD affects
disease progression. Currently, no clear recommendations about dementia prevention can
be made.

Secondary Prevention of AD
This refers to the prevention of development of AD in non-demented subjects with some
evidences of cognitive impairment. The groups most often studied in this regard are those
with Mild Cognitive Impairment (MCI) and several RCTs of ChEIs have been undertaken in
MCI, most using conversion to dementia as the primary outcome. A meta-analysis included
eight studies involving all three ChEIs, with duration of treatment ranging from 16 weeks to

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3 years [9]. There were no differences in rate of conversion to AD between active and placebo
groups, and most secondary outcomes were also negative. There have also been negative
studies of aspirin in primary prevention of cognitive decline and of anti-inflammatories and
vitamin E in MCI. A large study showed no effect of Gingko on preventing AD [10]. Therefore,
no treatments have demonstrated efficacy for preventing or delaying development of AD in
MCI subjects until now, while evidence exists that ChEIs, Vitamin E, Gingko Biloba and
anti-inflammatories are not substantively helpful.

Treatment of Established AD
There are currently no means of reversing the pathologic processes of AD.Currently
available medications do not halt the underlying degenerative process but can slow disease
progression and therefore delay symptomatic decline [11]. The specific goals of therapy are
to preserve cognitive and functional ability, minimize behavioral disturbances, and slow
disease progression with maintenance of patients and caregivers [12]. Nevertheless, realistic
expectations of treatment outcomes are needed because the impact for most patients is
likely to be modest and temporary, with not every patient responding to treatment. The
main benefit of pharmacotherapy is an attenuation of decline over time rather than an
improvement in cognitive or behavioral symptoms. It is important to discuss this point with
patients and their families, who mayexpect improvement rather than relative stability [13].
Failure to do so often will result in patient and family dissatisfaction with prescribed therapies
and the risk of discontinuation. Beneficial response to a ChEI (ie, delayed deterioration of
cognitive or behavioral problems) can be determined from the physician’s global assessment
of the patient, the primary caregiver’s report, a neuropsychologic assessment or mental
status questionnaire, or evidence of behavioral or functional changes [14].
Four drugs are commonly used for treating AD: Three ChEIs approved for mild to
moderate disease, one of which also is approved for severe AD, and a glutamate N-methyl
D-aspartate [NMDA] antagonist approved for moderate to severe disease.

Cholinesterase Inhibitors
Cholinesterase inhibitors increase cholinergic transmission at the synaptic cleft,
potentially benefiting patients with cholinergic deficits as in AD. Three such drugs are
currently available in the US: donepezil, rivastigmine, and galantamine. There has been
several well conducted placebo-controlled, large scale RCTs with this three ChEIs, which
have shown efficacy on cognitive function, global outcome and Activities of Daily Living (ADL)
in patients with mild to moderate AD, usually defined as MMSE between 16 and 26. Mean
global improvement over placebo is 3–4 points on the ADAS-Cog, a level of improvement
roughly equivalent to the naturalistic decline expected over a 6 month period. Most studies
have been over relatively short duration [6 months], though 1 and 3 year studies have been
reported with donepezil which suggest the benefits of ChEIs continue in the longer long.
Retrospective analysis and some long term open studies suggest a possible effect of ChEI
on disease modification, but more data are needed before this can be confirmed. RCTs of
ChEIs in more severe AD [MMSE < 10] have also shown positive results and a Cochrane
review concluded that trials supported evidence of benefit in mild, moderate and severe
AD [15-17]. In light of current evidence, limiting prescribing of ChEIs to only some AD
subjects according to certain cut-offs on a measure such as the MMSE, as operated in many
countries, does not seem justified. Although a point will be reached in severe AD when ChEI
are unlikely to continue to have benefit, it is currently unclear at what point in the disease
process ChEI should be withdrawn.
Rivastigmine is also approved for dementia in Parkinson’s disease. A large double-blind
placebo-controlled trial of rivastigmine showed meaningful improvements in cognition
andeveryday functioning [18].

48
 While there is expert consensus that cholinesterase inhibitors are more effective in
Dementia with Lewy Bodies (DLB) than in AD, for both cognitive and behavioral effects
,evidence from large controlled trials islacking [19].
In vascular dementia, evidence is mixed for the cholinesterase inhibitors. They are often
prescribed in vascular dementia because of the frequent co-occurrence of cerebrovascularand
neurodegenerative disease [19].
In frontotemporal dementia, there is no convincing evidence of benefits from these drugs,
and there are reports that they worsen behavior symptoms [20].
There is inadequate evidence on the use of cholinesterase inhibitors in other neurocognitive
disorders.Cholinesterase inhibitors (ChEIs) are generally well tolerated, although common
gastrointestinal adverse effects such as nausea, diarrhea, and vomiting may sometimes lead
to discontinuation of treatment in some patients.
There have been few direct comparisons between ChEIs, and those which have been
undertaken have been small in size and not produce consistent evidence of better efficacy of
one drug over another. There is some evidence from open-label studies that patients who do
not tolerate or do not seem to benefit from one ChEI may tolerate or draw benefit from the
other. One of the ChEIs, rivastigmine, is now available in a transdermal [patch] formulation
which appears to have lower incidence of side effects than oral administration but equal
efficacy [21].
A disease modifying effect of ChEIs has been proposed, and has some basic scientific
support, but no convincing clinical data, either from trials of clinical endpoints or of those
using biomarkers, has yet been forthcoming to support these claims.
Effects on non-cognitive Behavioural and Psychological Symptoms Of Dementia (BPSD)
have also been shown; though as with cognition effect sizes are modest. There remains
uncertainty as to which particular non-cognitive symptoms may respond best, though
effects on psychosis and apathy are consistently reported. Effects on agitation are less
clear, and a large placebo-controlled RCT in moderate to severe AD failed to show an effect
of donepezil on patients with clinically significant agitation [22].

Memantine
Memantine, a non-competitive N-methyl-D-aspartate receptor antagonist, also has been
subject to several RCTs in AD. It is believed to be neuroprotective against excitoxicity in the
cortex and hippocampus. Studies in moderate to severe AD have been more consistently
positive than those in mild to moderate AD, previous reviews of the literature have concluded
that while there is a significant effect in cognition at all severities, but effects on global
outcome, ADL and behaviour were only apparent in the moderate to severe studies [23].
Once daily dosing has been shown to be as effective as the original recommendation of
administration twice daily [24]. Modest effects on behaviour were also found in a pooled
analysis of six studies which included all those with MMSE < 20, with delusions, agitation/
aggression and irritability being the most responsive symptoms, though studies of subjects
primarily selected for the presence of these behavioural features have not yet been reported [25].
A systematic review showed that memantine had a small beneficial effect on cognition at
six months in moderate to severe AD, marginal effect on mild to moderate AD, and a small
but clinically undetectable effect in mild to moderate vascular dementia [26].
In frontotemporal dementia, memantine has shown mixed results. There is preliminary
evidence of benefits in DLB and Dementia in Parkinson’s disease; however, there have been
reports of worsening delusions and hallucinations in DLB.

49
 Combination therapy of a ChEI and memantine is rational from a pharmacologic
perspective because the agents have different mechanisms of action. In a randomized
controlled trial, patients with moderate to severe AD who were already receiving donepezil
derived significant benefit from the addition of memantine in terms of cognition, ADLs,
global outcome, and behavior [27]. There are also economic benefits associated with the
addition of memantine to donepezil treatment for patients with advanced AD. A recent study
demonstrated improvement in clinical outcomes plus cost savings associated with the use
of memantine [28]. In a study by Tariot et al, the incidence of nausea was substantially
lower in patients receiving memantine add-on therapy compared with those receiving
donepezil monotherapy [27]. The safety and tolerability of combining rivastigmine capsule
and memantine also has been studied in a 26-week, prospective, open-label study of
patients with moderate AD [29]. The combination was found to be both tolerable and safe,
with a reduced incidence of gastrointestinal- related AEs compared with those documented
in the US prescribing information for rivastigmine, suggesting that this beneficial effect of
memantine may be applicable across ChEIs [29].

Management of Mild to Moderate Disease

Since the introduction of the first ChEI in 1997, most clinicians would consider
these agents to be first-line pharmacotherapy for mild to moderate AD [30]. Four ChEIs
are currently available: tacrine, donepezil, rivastigmine, and galantamine. Tacrine is not
commonly used because of a poor tolerability profile and low oral bioavailability, and it is,
therefore, excluded from this discussion [21]. ChEIs raise acetylcholine levels in the brain by
inhibiting acetylcholinesterase [31]. Despite minor variations in their mode of action there
is no evidence to suggest any difference in efficacy between the 3 commonly used ChEIs
[30]. Likewise, the tolerability profile is similar between the ChEIs for the oral formulations.
However, the 10-cm2 rivastigmine patch has shown efficacy similar to oral rivastigmine
formulations, but with approximately two-thirds fewer reports of nausea and vomiting, with
Adverse Event [AE] rates similar to those of placebo [32]. AD often is accompanied and
worsened by malnutrition, and weight loss is a frequent complication of AD, occurring in
approximately 40% of patients at all stages [33]. Donepezil, rivastigmine, and galantamine
cause a broad spectrum of AEs, of which nausea, vomiting, diarrhea, and weight loss are
the most common [34, 35].
There continues to be debate regarding the extent of the benefits achieved with ChEIs.
Although some assert that the most that can be achieved with ChEIs is symptom modification,
others consider these agents to have disease-modifying effects [30,36]. In one study, after
discontinuation of therapy, rivastigmine treated patients showed less deterioration in
cognitive function compared with placebo treated patients, suggesting an effect on disease
progression [37]. In another study, donepezil treatment slowed progression of hippocampal
atrophy compared with untreated patients, suggesting a neuroprotective effect of donepezil
in AD [38]. However, these early observations require confirmation, and, at present, the
ChEIs generally are considered symptomatic medications.
A systematic analysis of double-blind, placebo controlled trials of ChEIs demonstrated
treatment effects ranging from a 1.4- to 3.9-point improvement at 6 months and 1 year, in
the midrange of the 70-point ADAS-Cog scale [30]. In clinical trials, a change of 4 points
is considered clinically significant for patients with mild to moderate dementia [39,40].
As such, the symptomatic improvements observed are modest and of debatable clinical
significance, despite being statistically significant [35]. In a meta-analysis of 16 double-
blind, placebo-controlled trials of ChEIs composed of almost 8000 patients, the numbers
needed to treat for one additional patient to benefit were 7 for stabilization or better, 12 for
minimal improvement or better, and 42 for marked improvement [41]. Although the numbers
needed to treat seem favorable, uncertainty remains regarding the clinical relevance of these
outcomes and the duration of the apparent benefit because the majority of trials reviewed
were of less than 26 weeks’ duration.

50
 In addition to their effects on cognition, these agents also have demonstrated beneficial
effects on measures of behavior, Activities of Daily Living (ADLs), and global patient function.
A recent meta-analysis that analyzed clinical results from 29 randomized, placebo-controlled
trials of patients with mild to moderate AD found that ChEI therapy was associated with
significant modest benefits in terms of neuropsychiatric and functional outcomes [42].
Current guidelines acknowledge that preventing or delaying further loss of ADL function is
an important goal of AD therapy and that the benefits of ChEIs may be diminished when
treatment is delayed [11,43]. Significant preservation of ADL function has been observed
with donepezil, galantamine, and rivastigmine compared with placebo [12].
ChEIs also have been shown to reduce AD caregiver burden: in patients with moderate
to severe AD, donepezil treatment for 24 weeks significantly reduced caregiver time spent
assisting patients with basic and instrumental ADLs (<52 minutes/day; P < .005) [44]. A
small study has demonstrated that rivastigmine treatment reduces caregiver time spent
assisting with ADLs (up to 690 hours over 2 years) [45]. Longer periods of treatment with
ChEIs also decrease the risk for nursing home placement [46,47]. A retrospective analysis
of a large US medical claims database showed that over a 27 months follow-up period, more
patients who were not treated with ChEIs were placed in nursing homes (11.0%) than were
those who received either rivastigmine (3.7%) or donepezil (4.4%) [47]. These studies suggest
that ChEIs enable patients to live longer in community settings with associated personal,
social, and economic benefits [12].
Memantine is sometimes used to treat patients with less severe disease, despite its use
in early AD not being supported by the FDA. Although memantine has been reported to
improve cognition, global status, and behavior in patients with mild to moderate AD, its
mechanism of action would suggest that it does not have a place in early AD [48]. Memantine
is not a ChEI; it is a low- to moderate affinity, noncompetitive [channel blocking], NMDA
receptor antagonist that seems to block pathologic neural toxicity associated with prolonged
glutamate release [49]. Blockade of NMDA receptors by memantine could confer disease-
modifying activity in AD by inhibiting the “weak” NMDA receptor–dependent excitotoxicity
that contributes to the neuronal loss underlying the progression of dementia [49]. As
such, memantine is not effective until weakened neurons become vulnerable to glutamate-
induced excitotoxicity, and therefore it cannot substitute for ChEIs because of its inability
to enhance cholinergic neurotransmission required for memory and learning [49].

Management of Moderate to Severe Disease

Memantine is approved for the treatment of moderate to severe AD on the basis of a study
in which patients with moderate to severe AD who received 20 mg memantine monotherapy
showed less decline in cognition and function while maintaining good tolerability after 6
months compared with those who received placebo [50]. The ChEI donepezil also recently
has been approved for use in severe AD.
Recently, donepezil 23 mg/day has been approved for the treatment of moderate to
severe AD. Results from a 24-week, randomized, double-blind study reported that donepezil
23 mg/day was associated with greater benefits in cognition (as assessed by the Severe
Impairment Battery) compared with donepezil 10 mg/day, although the between-treatment
difference in the Clinician’s Interview-Based Impression of Change plus Caregiver Input
Scale was not significant. The most commonly reported side effects with donepezil 23 mg/
day were nausea vomiting, and diarrhea, which occurred at a higher incidence than with
donepezil 10 mg/day [51]. Combination therapy of a ChEI and memantine is rational from
a pharmacologic perspective because the agents have different mechanisms of action. In a
randomized controlled trial, patients with moderate to severe AD who were already receiving
donepezil derived significant benefit from the addition of memantine in terms of cognition,
ADLs, global outcome, and behavior [27]. There are also economic benefits associated
with the addition of memantine to donepezil treatment for patients with advanced AD. A

51
recent study demonstrated improvement in clinical outcomes plus cost savings associated
with the use of memantine [28]. In a study by Tariot et al, the incidence of nausea was
substantially lower in patients receiving memantine add-on therapy compared with those
receiving donepezil monotherapy [27]. The safety and tolerability of combining rivastigmine
capsule and memantine also has been studied in a 26-week, prospective, open-label study
of patients with moderate AD [29]. The combination was found to be both tolerable and safe,
with a reduced incidence of gastrointestinal- related AEs compared with those documented
in the US prescribing information for rivastigmine, suggesting that this beneficial effect of
memantine may be applicable across ChEIs [29].

Other Drugs and Interventions

Several other treatments have been suggested as potentially beneficial for AD, including
non-steroidal antiinflammatory drugs, oestrogens and statins. A large, placebo-controlled
RCT of vitamin E (1000 IU, twice a day over 2 years) in moderate AD, was found to significantly
delay the time to a composite outcome of primary outcome measures, but a study in MCI
has been negative and the conclusion of a Cochrane review is that there is insufficient
evidence for the efficacy of vitamin E in the treatment of AD or MCI [52]. Studies of steroidal,
non-steroidal and cyclo-oxygenase-2 inhibitors in AD and MCI have been negative yet have
had potentially serious side effects.
Many other compounds, such as piracetam, nicergoline, selegiline, vinpocetine,
pentoxyphylins and Cerebrolysin are prescribed in some countries as treatments for AD.
For example, a recent Cochrane review of piracetam, one of the most widely studied drugs
to date, found poor study design, possible publication bias and that overall the evidence
from trials did not support the use of piracetam in people with dementia or cognitive
impairment [53]. A review of 6 Cerebrolysin trials found an effect on global outcome but no
consistent effect on other scales. Further evidence is therefore required before its use can
be recommended [54]. Similarly, a Cochrane review of selegiline found no evidence for its
efficacy in AD [55]. At present, therefore, there is no convincing evidence for efficacy of any
of these drugs for AD.

Management of Behavioural and Psychological Symptoms

Management of BPSD begins with careful search for trigger and/or exacerbating factors
that including environmental cues, physical problems [infections, constipation], medication
and depression or psychosis. As studies of BPSD indicate a high placebo response, safe non-
pharmacological management [education, exercise, aromatherapy, sensory stimulation,
personalised music] should be tried wherever possible in the first instance as symptoms
may naturally resolve within a short time. The beneficial effects of ChEIs and memantine
for mild BPSD have been described above, but a recent RCT found donepezil did not help
clinically significant agitation in those with moderate to severe AD [22].Both conventional and
atypical antipsychotics reduce BPSD, with particular effects demonstrated for risperidone
for agitation/aggression and psychosis [56,57]. However, antipsychotics have important and
potentially serious side effects, most especially increased stroke risk, increased mortality,
parkinsonism and cognitive impairment [58]. They should be used with caution, at low dose,
and for the shortest period needed only for those with moderate to severe symptoms causing
distress and after careful assessment of risk and benefit and after discussion with care-giver
and, where possible, patient. There is no evidence that conventional agents are any safer in
regard to risk of stroke or mortality than atypical agents and they have a less established
evidence base and greater side effects [59]. Low doses of antipsychotics should be used with
careful monitoring, and drugs prescribed for the minimum period required. When BPSD
have settled, antipsychotics can be withdrawn in most cases without re-emergence of BPSD,
unless behavioural disturbance is still present [60]. Evidence for other drugs is limited,
carbamazepine may help aggression, though most studies of valproate have been negative

52
[61,62]. Antidepressants, especially Selective serotonin reuptake inhibitors [SSRIs], may
be useful for depression in dementia and do not have the adverse anticholinergic effects of
older tricyclics [63].

Duration of Management
Placebo-controlled clinical trials with marketed cholinesterase inhibitors generally have
lasted 6 months, with a few exceptions lasting up to 12 months or longer. Inferences are
made that if the drugs are effective over this period then they will continue to be beneficial
far longer, perhaps indefinitely. Over the long term, however, as patients inevitably worsen,
it becomes even more difficult to determine whether any given individual is benefiting from
the drugs.
In some 3-month-long and 6-monthlong trials, after medication has been discontinued
patients on average return to the cognitive level of the patients contemporaneously treated
with placebo within 6 weeks. Such findings are taken to indicate that the drugs have overall
symptomatic effects and that continuous use is required to maintain benefits.
Some observational studies using clinic databases or open-label extensions of clinical
trials suggest that patients who continue cholinesterase inhibitors over at least 1 year
have a delay in nursing-home placement compared to those who cannot tolerate or do not
take them, and that the addition of memantine could further contribute to the delay [64-
67]. These observations, however, are not controlled and are subject to the potential bias
that patients who experience a lessprogressive course continue their medications, while
patients who are destined to progress more quickly do not continue, resulting in apparent
therapeutic effects that are illusory. Moreover, comparisons are made between cohorts from
time periods both before and after the ready availability of the cholinesterase inhibitors
[68]. These observational studies, however, contrast with the long-term controlled trials in
MCI and with observations from the Australian Imaging Biomarkers and Lifestyle datasets,
where the use of cholinesterase inhibitors over the long term is associated with faster decline
[69,70]. Thus, duration of treatment remains an unresolved issue.

Withdrawal of Cholinesterase Inhibitors or Memantine

Discontinuation of cholinesterase inhibitors has been associated with worsening of
cognition and confusion in some patients. This effect was evident in a clinical trial in which
donepezil was stopped after a fixed period of 12 weeks and patients were then randomized
to continuing drug or to placebo as well as when patients were discontinued from some
6-month trials [71]. Yet worsening of behavior and confusion do not appear common when
the drugs are stopped in clinical practice, as is frequently done. In clinical practice only 19%
to 23% of patients continued to take donepezil or rivastigmine for more than 1 year, and
about one-third discontinued the drugs within 2 months [72].
Tapering and withdrawal of donepezil after maintenance treatment for an average of 2
to 3 years was formally tested in a randomized controlled trial of severely impaired patients
with Alzheimer disease; continuing donepezil was compared with discontinuing it, and,
simultaneously, starting memantine was compared with not starting it [73]. Over the 1-year
follow-up period, continuing donepezil was associated with better cognitive scores and
ADLs, and adding memantine when donepezil was discontinued was better than not adding
it. Many patients, however, discontinued donepezil without difficulty; notably, only half of
the patients who were assigned to continue donepezil actually continued treatment beyond
the 1-year follow-up, suggesting that many patients perceived that continuing donepezil,
at least under double blinded conditions, was not effective. Thus, the outcomes support
decisions either to continue medication or to taper and discontinue it when physicians
are uncertain of continuing benefit [74]. This trial also did not support the typical use
for memantine as an add-on to donepezil, showing that the add-on was not better than

53
continuing donepezil alone, a finding that adds to the controversy of whether the drugs
taken together are better than either alone. It is generally good practice to taper these
medications before discontinuing, even though both donepezil and memantine have long
terminal half-lives.

Future Therapeutic Approaches and Management of Ad

There are three foots on AD course modifying research.
First is to select high-risk population with current evidence and to provide primary
prevention. This step aims to manage modifiable risk factors [75]. Second is to diagnose
patient at preclinical phase, which took 10-20 years before symptoms occur. Researchers
focus on new neuroimaging techniques, new laboratory and CSF investigations and genetic
studies [75]. Third is to discover disease-modifying molecules. Studies are mainly focused
on: [1] to inhibit extracellular amyloid plaque accumulation and to inhibit intracellular tau
based neurofibrillary tangles accumulation [75,76].
Anti-amyloid agents
The initial process of AD is not determined yet, but one of the main proposed
pathophysiological processes is ‘Amyloid Cascade Hypothesis’. All autosomal dominant AD
genetic forms are due to mutations of amyloid metabolism encoding genes. Although ‘Amyloid
Cascade Hypothesis’ does not capture all aspects of disease process, there is clinical and
experimental data showing toxic effects of accumulated amyloid plaques. Focused amyloid-
directed therapies could be divided to three classes including secretase modulators, amyloid
anti-aggregants and immunotherapies [77].
Secretase modulators
To decrease Aβ production, research aimed to modulate enzymes that breakdown amyloid
precursor protein [by stimulating α secretase or inhibiting γ and β secretase activity].
Whereas effective α secretase was infrequently identified, numerous γ and β secretase
inhibitors developed. γ secretase have critical role in Aβ generation but this enzyme has
multiple cleavage actions including notch receptor signaling and thought to have important
side effects. Currently developed β secretase inhibitors also failed to show disease-modifying
effects but there are still ongoing researches [78].
Amyloid anti-aggregants
Another point is to prevent aggregation of amyloid in non-soluble forms. It’s known that
Aβ forms oligomers, fibrils and then deposition of amyloid plaques exists. New studies also
report soluble form of Aβ have also toxic effects. Tramiprosate, colotrinin, clioquinol are
some of the studied anti-Aβ aggregation agents. Phase II and III studies showed conflicting
results, including no effects and minimal effects. There are ongoing studies to research
current molecules and to develop new molecules [78,79].
Amyloid removal [Immunotherapy]
Although there is no proven exact mechanism how immunotherapy might attenuate Aβ
plaques in the brain, some mechanisms have postulated. Therapeutic aim is to induce a
humoral immune response to fibrillary-Aβ42 or passive administration of anti Aβ antibodies.
First studies of active vaccination were halted due to induction of serious side effects-
meningoencephalitis. There are alternative new molecules developed and ongoing Phase
I-III trials with active and passive immunization (CAD106, Bapineuzumab, Solanezumab,
Intravenous Immunoglobulin) [80, 81].
Tau-based therapies
Hyperphosporylated tau aggregates in neurons and forms neurofibrillary tangles [NFT],
lastly causes neuronal death in AD. Tau is a microtubule- associated protein and encoded

54
by the MAPT gene and has functions like, to assemble microtubules and regulate axonal
transport. Hyperphosporylated tau has been shown to cause, disruption of mitochondrial
respiration and axonal transport. It’s important to emphasize that tau hyperphosphorylation
is also regarded as pathologic hallmark of other neurodegenerative diseases, including Pick
disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal
dementia with parkinsonism (FTD-P). FTD-P is caused by mutations of tau encoded MAPT1
gene. Thus support tau dysfunction could drive neurodegeneration without amyloid
deposition [82]. Tau based therapies are still at conceptual stages and include passive
immunization against tau, preventing tau hyperphosphorylation and anti-aggregants of
tau. Methylthioninium chloride and lithium are some of the agents with ongoing studies.
There are also some trials ongoing about anti-tau vaccines at AD [83,84].
Name Company Phase Antigen
Affitope AD02 Affiris/GlaxoSmithKline II Aβ1–6
CAD106 Novartis II Aβ1–6
Vanutide cridificar Elan/Johnson & Johnson/Pfizer Inc. II Aβ1–6
AC Immune/Bayer Healthcare
ACI24 I / II Aβ1–15
Pharmaceuticals
V950 Merck & Co. I Not published
Affitope AD03 Affiris/GlaxoSmithKline I Pyroglutamate modified
Aβ UB311 United Biomedical I Aβ1–14
AN1792 Elan Terminated Aβ1–42
Aβ, amyloid-beta.
Table 1: Ongoing and terminated active amyloid-beta immunotherapy clinical programs in Alzheimer’s disease [85].

Name Company Phase Trial population Binding domain Target

Solanezumab Eli Lilly and Company III Prodromal and mild AD Aβ16–23 Soluble Aβ
Gantenerumab Roche 2/3 Prodromal and mild AD conformational Aggregated Aβ
Eisai/ BioArctic MCI due to AD or mild
BAN2401 2b conformational Soluble Aβ protofibrils
Neuroscience/Eisai AD
Prodromal and mild/ Soluble oligomeric/
Crenezumab Genentech/Roche 2 Aβ 12-23
moderate AD fibrillar Aβ and plaque
Intravenous
and
Elan/ Pfizer Inc./ Johnson Soluble and
Bapineuzumab subcutaneous Mild/moderate AD Aβ1–5
& Johnson aggregated Aβ
programs
terminated
Biogen Idec/
MCI due to AD or mild Conformational
BIIB037 Neuroimmune 1 Fibrillar Aβ
AD Aβ
Therapeutics
Soluble and
AAB003 Elan/Pfizer Inc./ Janssen 1 Mild/moderate AD Aβ1–6
aggregated Aβ
Soluble oligomeric/
SAR228810 Sanofi 1 Mild/moderate AD Not published
protofibrillar Aβ
Catalytic
ABP102 Abiogen Pharma 1 AD antibody Aggregated Aβ
cleaving Aβ
Soluble and
Ponezumaba Pfizer Inc. 1 Mild/moderate AD Aβ33–40
aggregated Aβ
Aβ, amyloid-beta; AD, Alzheimer’s disease; MCI, mild cognitive impairment.
Table 2: Ongoing and terminated passive immunotherapy clinical programs in Alzheimer’s disease [85].

As for conclusion, Aβ immunotherapy has gained a lot of attention and emerges as one of
the most attractive approaches for disease intervention in AD. Aβ neurotoxicity has been shown
to be caused by soluble protofibrils rather than insoluble fibrils, and this highlights protofibrils
as targets for immunotherapy. Other encouraging efforts in immunotherapy as well as in the
small-molecule field offer hope for new innovative therapies for AD in the future.

55
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 eBooks

Common Medical Problems in Patients with

Alzheimer’s Disease
Mahir Cengiz*
1
Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine,
Istanbul, Turkey

Corresponding author: Mahir Cengiz Istanbul University Cerrahpasa Medical Faculty,

*

Department of Internal Medicine, Istanbul, Turkey E-mail: drmahirc@yahoo.com

Abstract
Elderly persons are at increased risk for developing dementia, and this risk increases with
age. Alzheimer’s disease is the most common disease of dementia and is characterized by a
gradual progression of cognitive impairment that interferes with the patient’s independent
activities of daily living. Alzheimer’s disease has severe effects not only on patients but
also on their caregivers. Alzheimer’s disease is a growing health issue characterized by
declines in brain functions that are irreversible and is one of leading causes of death among
elderly people. Alzheimer’s disease is a disease that both accelerates the physiological
changes due to the old ages and masks those changes with the deterioration in cognitive
function developing together with it. Fallings, urinary and fecal incontinence, pressure ulcer
ulceration, infections, polypharmacy and thromboembolic events are the most common
reasons of the mortality and morbidity in elderly patients with Alzheimer’s disease. For
the early diagnose of these events and the optimum management of elderly patients with
Alzheimer Disease, comprehensive geriatric assessment should be recommended.

Keywords: Aging; Alzheimer’s Disease; Geriatric Assessment

Introduction
Alzheimer Disease (AD) is prevalence of which is very high in geriatric population and
is characterized by loss of cognitive and social functions so that can affect the daily life
of the person. It is estimated that the disease affects 24 million of people worldwide and
this number will be reached to 80 million by 2040 [1]. It is reported that prevalence of the
disease is 13% and 43% among the people older than 65 and 85 respectively in USA. While
in Europe the prevalence of AD is 0.3% among the people of ages between 60-65, this
number reaches 10.8% among the people of ages between 80-89 [2,3]. Prevalence of AD
among the people aged 70 years and over in Turkey has been determined as 11% by Turkish
Alzheimer’s Prevalence Study. According to this value, it is predicted that there are 250.000-
300.000 patients with AD in Turkey [4].
Along with deterioration of cognitive functions which is significant especially during
stress period and senility, decrease in organ system reserves, homeostatic control and

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ability to adapt to environmental factors may result in impaired stress capacity. This kind
of processes makes the patients vulnerable to traumatization/physical injuries and many
diseases. Particularly the cases like urinary and fecal incontinence, falls, decubitus ulcers/
pressure sores, malnutrition, infections and polypharmacy raise morbidity and mortality.

The Urinary and Fecal Incontinence

In the general population prevalence of incontinence rises with age, with estimates of up
to 15% of older women and 2-11% for older man experiencing daily urinary incontinence,
with higher rates for those living in care homes [5]. Prevalence of fecal incontinence among
people aged over 60 is 5.1% in man and 6.2% in women [6]. Urinary incontinence in
patients with AD results from the coming together of impaired cognitive functions, neuro-
urinary pathologies, age-related changes, comorbidities and multifactorial reasons due to
medical therapies [7].
Disappearance of central cortical inhibitory effect on sacral micturition leads to
incontinence in AD [8]. Along with this, age-related decreased post-menopausal estrogen
levels, decreased urethral pressure, prostatic hypertrophy, changes in bladder functions
and to be susceptible to infections due to impaired immune functions precipitate urinary
incontinence in these patients. The reason why urinary incontinence is so important is that
It may cause lots of complications; particularly psychosocial complications. It may lead
to a range of complications like maceration and irritation signs on skin, decubitus ulcers
especially in patients confined to bed or a wheelchair, infections and delayed healing of the
pressure sore or surgical wounds [9]. Urinary continence, which is a very unpleasant and
hard situation for patient, healthcare personnel and family members who are responsible for
the patient’s care, is one of the most important indications in USA and Northern European
countries to put an elderly person in a nursing home [10]. In a study, have emphasized
in one of their studies performed on geriatric cases with overactive bladder that trospium
can be a good option for the treatment because of its suitability for polypharmacy, less
side effect profile and high effectiveness [11]. This study is important because it shows
us trospium unlike other bladder antimuscarinics does not have any negative effects on
cognitive process in patients with late-onset Alzheimer disease.
In addition to this, it can be said that it affects cognitive process positively by boosting the
wellbeing in the patient with both urge incontinence and AD in order to make them regain
their autonomy. Another thing we should consider is this wellbeing issue also contributes
the caregivers doubtlessly. This favorable effect is possible results from low lipophilicity and
poor penetration of trospium through blood brain barrier. Because of the same reason, fewer
central system side effects are seen in the cases [12, 13]. In the case of recoverable reasons,
the underlying pathologies should be treated, however in chronic urinary incontinence;
medical, surgical or rehabilitative treatment should be applied accordingly to incontinence
type of the patient [7].

Falls
Falls, one of the geriatric syndrome, is an important health problem that leads to
limitation of mobility, dependency in activities of daily living, increased need for institutional
care and threats independency of elderly persons [14]. In USA, falls are responsible for 5.3%
of all hospitalized elderly patients. Falls are one of the most serious and most frequently
seen problems that elderly patients encounter. In a study, it is indicated that 35% of people
over 65 and 50% of people over 85 falls every year [15]. Falls are more commonly seen
in elderly people living in nursing homes. 50% of elderly people staying at institutes for
healthcare falls at least once in a year, and 40% of them falls more than once in a year.
Incidence of falls in institutes is 1.5 per bed annually [16]. Increase in falls incidence in
patients with Alzheimer Disease results from multiple factors like impaired muscle power,
decreased visual and auditory functions, decreased proprioception, shortened of reaction

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time. Risk factors for falls that are commonly seen in patients with AD and other older
populations are classified as individual and environmental risk factors [17]. Individual
risk factors are side effects of medicines, balance problems, muscle weakness, sensational
impairments, decreased cognitive functions and communication, senility and concomitant
disorders. Inadequate lighting, objects that may cause stumbling, inappropriately high and
large stairs, irregular or wet floors are named as the environmental factors [18].
In patients with Alzheimer Disease, balance and coordination are impaired by progression
of the disease. Balance means an ability to provide body control on a supportive floor to
prevent falls. In patients with AD, loss of balance and falls are commonly encountered due
affected afferent and efferent mechanisms that maintain the balance [19].
Some strategies has been planned to prevent falls, and generally most of them are
about environmental risk factors. The measures aimed changes in physical environment
are accepted one of the most successful strategies. Along with concomitant disorders,
immobility after falls in patients with AD increases the mortality. Immobility is an important
issue because it may cause impaired hygiene and infections like pulmonary pathologies and
decubitus ulcers. To evaluate a patient with a history of falls or a patient with fall risks;
reason of falls, pattern of falls, medical history, evaluation of vision, neurologic assessment,
skeletal system assessment and cardiovascular evaluation are should be done carefully.
Because falls can be early sign of a disease, a detailed geriatric assessment is extremely
important.

Decubitus Ulcers
Decubitus ulcers are lesions that formed by long term pressure application on an underlying
tissue. Generally it results from compression of soft tissues between bony processes and external
surfaces. Pressure sore can be seen as a superficial erythematous lesions or a deep ulcer that
can reach the bone. 95% of decubitus ulcers appear on protrusions at lower body. They are
most commonly seen at ischium (28%), sacrum (17-27%), trochanter (12-19%), and heels
(9-18%) [20,21]. One of the predisposing factors of pressure ulcers is Alzheimer disease and
decubitus ulcer is a geriatric syndrome that especially seen in later stage of the disease. Along
with cognitive impairment in patients, urinary and fecal incontinence, malnutrition, infections
facilitated pressure ulcers to be formed. In addition, so do suboptimal care conditions [20-22].
Measures to prevent decubitus ulcer should be considered as soon as risk factors appear.
An effective preventive program consists of a medical care, a good nursery care, an appropriate
education, a reinforced patient and relative’s compliance, and application of appropriate
decompressive devices. Decubitus ulcers are more commonly seen in patients hospitalized or
in patients in nursing homes [22]. Concomitant comorbid diseases of patients are effective on
both of progression and healing process of lesions. Regular skincare should be done in patients
with AD. Skin should be kept clear, not dry and it should be moisturized by appropriate creams
and oils. As they are dependent, the patients with AD have a tendency to malnutrition. Special
attention should be paid to their nutritional state and positive nitrogen balance should be
maintained. 1.5-2 g/day protein should be given [23]. Nutritional state of the patients, albumin
and prealbumin levels should be followed up regularly. In some studies, it has been showed
that vitamin C supplementation is effective in patients with decubitus ulcers. As zinc is required
for protein synthesis, it should be replaced and pomades including zinc should be applied on
macerated areas. Position changes in every 2 hours are key to preventing pressure sores. Also
special beds and cushions can be helpful to decrease pressure [24].

Malnutrition
In patients with AD, malnutrition is seen more commonly. That is because of impaired
cognitive functions, impaired deglutition and changes in sense of taste [25]. In addition to
these factors, age-related physiologic and functional changes and other changes in daily

63
life may precipitate malnutrition. Energy requirements in senescent period are less than
in adulthood. But it may increase in case of diseases, mutilation/injuries or fractures. In
these kinds of cases, if the patient can not be nourished sufficiently, it may cause chronic
nutritional deficiency. Malnutrition leads to increase in incidence of chronic diseases and
mortality in these chronic diseases. Under normal circumstances, energy requirement in
an elderly is 30 calorie/kg or at least 1200 calorie/day [26,27]. In general, health problems
like infections, operations, injuries and fractures increase protein requirements. If we
consider age related decreased immune system functions, 1 gr/kg protein may be sufficient
for a day. In some cases like chronic kidney disease, protein intake must be limited, it is
arranged accordingly [28]. 60% of daily energy intake should come from carbohydrates.
It is important to take sufficient carbohydrate, as its deficiency leads to use of proteins
as an energy source. But overconsumption of carbohydrates causes being overweight by
transformation of carbohydrates to lipids. Carbohydrate requirements should be met from
cereals, bran cereal flour, vegetables and fruits [27]. Vitamin and mineral requirements
increase in senescent period due to decreased energy demand, impaired body resistance,
movement restriction and increase in incidence of chronic diseases. Vitamin and mineral
deficiencies affect progression of acute and chronic diseases and may lead to deaths. If
there is no special health problem preventing usage of vitamin and minerals in body, or no
limitation of nutritional intake, vitamin and mineral needs with exception of vitamin D can
be met from a good arranged diet. As overconsumption of some vitamin and minerals may
cause toxic effects, supplements should be taken by advisement of doctors and dieticians.
If there is no any necessity, requirements should be met from foods. The body losses
approximately 2.5 liters of water (15-20 glasses of water) by urine, stool and respiration
everyday. This loss should be replaced. Because body fluid loss increases in the case of hot
weather, heavy exercise, fever, diarrhea and consumption of foods rich in protein and salt,
amount of fluid intake needs to be increased. During senescent period of life at least 8-10
glasses of water (1500 milliliter) should be consumed [26].
When malnutrition takes place in a patient, it is almost always together with prominent
protein degradation, loss of endogenous protein stores, decline in organ and muscle weight,
impaired immune response. These kinds of changes lead to patient to need more intense
care and respiratory support, to become infected with nosocomial agents which are one of
the important reasons of mortality due to septic shock and multiple organ dysfunctions.
With an early nutritional support, it is possible to control metabolic changes in elderly by
altering the cytokine response against primary disease that causes stress in organism. It’s
recommended that enteral nutrition should be continued in patients with AD. It provides
protection of structural and functional integrity of small intestine. Intestinal atrophy due to
enteral nutrition discontinuation increases permeability of bacteria and endotoxins and it
becomes a risk factor for infection and systemic metabolic changes [29].

Infections
Immune response shows decline with age. Along with this decline, malnutrition, poor
personal hygiene, problems with swallowing make the patients with AD more susceptible
to infections, and make the infections that already developed to be more serious. Basically
Urinary Tract Infections (UTI) and respiratory system infections are common in patients
with AD [30]. In elderly people, description, diagnosis and management of UTI are extremely
complicated. In elderly, this kind of infections may cause some unspecific symptoms
like anorexia, weakness, etc., may lead to chronic genitourinary symptoms such as
incontinence, and also make Alzheimer worse. That’s why even asymptomatic bacteriuria
is treated nowadays. However, it is a fact that urinary tract infections in patients with AD
cause a prominent increase in morbidity and mortality. Dysuria, frequency and urgency are
common symptoms but they should be assessed carefully, because they can be seen without
an infection [17]. Alzheimer’s patients who have urinary tract infection need to be treated
but diagnosis should be relying on a careful clinical assessment. A positive urine culture

64
may not be a sign of a true urinary tract infection. Because culture can not discriminate
colonization and contamination. That’s why specialists should treat the patients, not
the culture results to prevent irrational use of antibiotics. Interestingly, some specialists
recommend urinary cultures in elderly people just to confirm antimicrobial susceptibility.
Asymptomatic bacteriuria needs to be scanned and treated only in selected populations. If
there is no benefit shown, it is recommended that antimicrobial therapy should be avoided [30].
Respiratory system infections especially pneumonia is an important cause of death
in people over 65 in developed and developing countries. In elderly people, pneumonia is
among the first 10 leading causes of death. Even the cases whoes are healthy otherwise or
the cases with low risk factors can be susceptible to respiratory system infections due to
the changes in immune system. Age related decline in immune system against infection
agents such as influenza virus and Streptococcus pneumoniae that required antigen
specific immune response (adaptive-innate immunity) is most important reason of this
susceptibility. Vaccination of elderly adults, especially pneumococcal vaccination, is very
important [31]. Along with these facts, it is reported that atypical antipsychotics which are
used for the treatment of behavioral disturbances in Alzheimer’s patients, increase the risk
for pneumonia and hip fracture [32].

Polypharmacy
A grade number of medicine use may lead to some problems such as serious side effects,
drug-drug interactions and this may cause poor compliance to treatment. Alzheimer’s
patients generally expose to polypharmacy, because they have comorbidities due to advanced
age and need to be assessed by number of different specialists. Decrease in saliva and
stomach motility is seen in Alzheimer’s patients with increasing age. Decline in splanchnic
blood flow, changes in body composition, %30 declines in blood flow to kidneys and liver
parenchyma, approximately 8-10 ml/min decrease in glomerular filtration rate after age
of 30 take place. This situation changes drug pharmacodynamics and pharmacokinetics.
Along with toxic effects of polypharmacy, drug-drug interactions may lead to decrease in
the expected benefit and exacerbate toxicity. That’s why all the medicines patient is on
should be assessed one by one at every visit, and ones that patient’s going to take should
be marked. Appropriate storage conditions for medicines should be provided to prevent
forgetting and taking more than need [7].
As a result, Alzheimer Disease is a disease that has an increasing incidence concordant
with increasing number of elderly population, and can be diagnosed with 90% probability
by using combination of detailed and careful history taking, physical examination and
laboratory techniques. The internal problems that added to heterogeneous neurologic
profile of the disease make the clinical presentation very complicated. This complicated
presentation which may lead to delayed medical diagnosis and treatment, can cause death
of Alzheimer’ patient. Overcoming of some problems with a good communication with
patient, a qualified follow-up of patient’s medical records, knowing very well the patients
and her/his relatives, detailed assessment at every visit and relatives’ efforts provide more
comfortable and healthy life to the patients with Alzheimer disease.

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 eBooks

Nutritional Condsiderations in Patients with

Alzheimer’s Disease
Serap Yavuzer (MD)*
1
Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine,
Istanbul, Turkey

*
Corresponding author: Istanbul University Cerrahpasa Medical Faculty, Department of
Internal Medicine, Istanbul, Turkey, E-mail: drserapsahin@gmail.com

Abstract
Alzheimer’s Disease (AD) is the most common type of dementia that is more commonly
seen in advanced age group. The most important risk factors for AD are known as aging and
genetic predisposition. However there are many modifiable risk factors such as especially
obesity, hypertension, hypercholesterolemia, diabetes mellitus, alcohol, smoking and low
physical activity leading to AD. Recently, it has been reported by several studies that some
dietary factors like antioxidants, vitamins, polyphenols and fish decrease the risk of AD,
while fatty acids, high calorie intake and alcohol consumption increase the risk of AD.
Although there is no special diet to prevent AD, positive effects of Mediterranean diet has
been shown. It is also very important to follow up body weight, evaluate the nutritional
state in elderly people and inform the relatives about AD, because decline at body weight in
patients may occur before the diagnosis. Evaluation of nutritional status should be provided
in every stage of the disease. In addition, loss of appetite, weight loss and disphagia should
be determined on time, and nutrition support therapy should be started immediately. When
approaching to the nutritional problems due to aging and AD, participation of caregivers
and relatives should be provided during management. In this section, role of nutrition on
development and prevention of AD which is a very important disease of geriatric population,
and nutritional problems that AD patients and caregivers encounter will be tried to explain.

Keywords: Alzheimer’s Disease; Diet; Nutrition

Introduction
Alzheimer’s Disease (AD) is the most common type of dementia in the world that is a
progressive neurodegenerative disease and more commonly seen in advanced age group. It
constitutes 60-80% of all cases with dementia. It was determined that 4.7 million people
in United State of America (USA) have Azheimer’s Disease in 2010. It is reported that
the prevalence of the disease is 13% and 43% among the people older than 65 and 85
respectively in USA [1]. In Europe, the prevalence of AD is 0.3% among the people of ages
between 60-65, this number reaches 10.8% among the people of ages between 80-89 [2]. It
is predicted that the number of cases with AD will reach 100 million worldwide by 2050 and
lead to a serious socioeconomic burden [3,4].

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 The most important risk factors for onset and progression of AD are aging and
genetic predisposition (presence of epsilon 4 allele of apoprotein E gene). However it is
determined that there are many modifiable risk factors leading to AD. By epidemiologic
researches it has been demonstrated that low level of education, depression and especially
cardiovascular risk factors such as obesity, hypertension, hypercholesterolemia, diabetes
mellitus, alcohol, smoking and low physical activity increase the risk of AD and dementia
[5-7]. In recent years numerous proofs on association between nutrition and AD have been
provided. For instance, it has been reported that some dietary factors like antioxidants,
vitamins, polyphenols and fish decrease the risk of AD, while fatty acids, high calorie intake
and alcohol consumption increase the risk of AD [8].
Since AD develops in advanced ages, the feeding problems from disease’s process and
nutritional problems due to aging overlap. Therefore health status and life quality of both
caregivers and patients are affected unfavorably.
In this section, role of nutrition on development and prevention of AD which is a very
important disease of geriatric population and nutritional problems that AD patients and
caregivers encounter will be tried to explain.

The Association between Alzheimer’s Disease and Nourishment

There are many studies exploring the relation between AD and obesity. In spite of
discrepancy of some results, most of them indicate us obesity may be a risk factor for AD.
Actually low Body Mass Index (BMI) was reported as a risk factor for dementia long years
ago [9]. It has discovered that both low and overweight increase risk of AD age relatedly
by a comprehensive and prospective research made in recent times [10]. The presence of
a relation between obesity-overweight and AD has been reported in many studies [11-13].
However, the evidence relating obesity measured with Body Mass Index (BMI) with AD is
conflicting. Obesity (BMI> 30 kg/m2) in midlife has been found to increase the risk of AD,
whereas late-life obesity has been found to reduce the risk of AD [11]. It’s reported that
the people with BMI>30 kg/m2 in their midlife have 35% higher risk of dementia than the
people having normal BMI in another research made by Profenno et al., This result makes
us predict that increase in prevalence of obesity may increase incidence of AD in the future [14].
When relation between AD and weight loss-malnutrition is investigated, we realize that
it is a complication developing through the disease process rather than a risk factor. This
relation will be discussed in the fifth section named as Malnutrition in AD.

The Association between Nutrition and the Risk of Alzheimer’s Disease

The pathophysiology of AD that is extremely complicated, consists of oxidative and
inflammatory pathways and hormonal effects. Especially the enhancement in oxidative
stress damages brain functions by increasing reactive oxygen species. When the association
between nutrition and onset and progression of AD is investigated, it is reported that some
nutrients like antioxidants, vitamins, fatty acids and carbohydrates increase the risk of
AD. Although it is estimated that nutrient’s effects on AD are based on decreasing oxidative
stress and amyloid beta (Aβ) deposition pathways, the exact mechanisms are not clear yet
[15,16].
Antioxidants
Vitamin A and β-carotene: they are considered as important factors for prevention and
treatment of AD because of their effects on inhibition of both Aβ oligomer and fibril production
[17]. Plasma and serum levels of these vitamins have been found low in patients with AD
[18,19]. Furthermore, in another study performed on elderly people, it’s been reported that
higher β-carotene plasma levels are related with better memory performance [20]. However,
data on the supplementation of only vitamin A in patient with AD were not available.

69
 Vitamin C: it has been proven in vitro and in vivo, it decreases Aβ oligomer formation
and oxidative stress [21,22]. However the relation between AD and vitamin C is not clear
yet. Although the relation between decreased incidence and prevalence of AD and combined
use of vitamin C and vitamin E for at least 3 years has been determined, an association
between use of only vitamin C and risk of AD couldn’t be found by other prospective studies
performed on large number of people [23-25]. As a result of these studies, it is predicted
that precautions against vitamin C deficiency is more protective than supplemental vitamin
C intake in addition to on a normal health diet [26].
Vitamin E (Alpha-tocopherol): it has been shown that Vitamin E protects cognitive
functions by decreasing oxidative stress and clearing Aβ related free radicals [27-29].
Vitamin E occurs naturally in the form of tocopherols and tocotrienols. It is found in many
foods, including mangoes, papayas, apples, avocadoes, tomatoes, red bell peppers, and
spinaches, and particularly in high quantities in nuts, seeds, and oils. A positive relation
is determined between especially high intake of a-tocopherols and 𝛾-tocopherols which are
Vitamin E forms and decrease in incidence of AD [30]. Lower total vitamin E levels are
found in patients with AD and moderate cognitive impairment when compared with normal
individuals [31]. Because of Vitamin E from supplements has not been shown to reduce
Alzheimer’s disease risk, Vitamin E should come from foods, rather than supplements.
Recommended amount of Vitamin E is 15 milligram for an adult [32]. As exact benefit of
Vitamin E on prevention and treatment of AD has not been proved, routine Vitamin E intake
is not recommended.
Selenium: has been reported to play an important role in the antioxidative defense
[33]. In some studies it was shown that supplementations of selenium-containing mixtures
improved cognition [34, 35]. AD patients showed a significant lower Selenium level in plasma,
erythrocytes, and nails when compared to controls [36]. Current knowledge provides no
proof of a role of selenium (Se) in the treatment of AD. It is not clear that the low level of
selenium in patient with AD whether is a reason or a result of the disease like in many other
nutrient levels. Therefore more research is needed to explain the association of selenium
with the risk of AD [37].
Ferulic acid, polyphenols (Quersetin, resveratrol), alpha lipoic acid, N-acetyl-
L-cystein, curcumin, epigallocatechin gallate, gingko biloba and gamma-glutamyl
cystein ethyl ester: are another antioxidants stated that may prevent, delay and treat
AD [38]. It is predicted that polyphenols have beneficial effects on cognitive functions and
it’s been demonstrated by inhibition of Aβ formation in animal studies and by decreasing
homocysteine concentrations in clinical studies performed on patients with AD [39,42].
There are many foods that include these antioxidants naturally in our diet; for instance;
querstein in green tea, onion and apple; resveratrol in grapes used in red wine production,
curcumin in turmeric; epigallocatechin gallate in black and green tea; vegetables, fruits,
cereals in especially wheat; ferulic acid in eucalyptus, etc.
B Vitamins
Folic acid, Vitamin B6 (pyridoxine) and B12: it is estimated that they have roles in
pathophysiology of AD by decreasing homocystein level and inhibiting oxidative stress
[43,44]. It is reported that every 5 mmol/Lt increase in homocystein level raises the risk
of AD by 40% [45]. Because high level of homocystein and low folate and B12 levels are
determined in patient with AD, a number of researches on this association have been made
[46,48]. In a recently performed randomized placebo-controlled trial, 0.8 mg folic acid, 0.5
mg vitamin B12, and 20 mg vitamin B6 or placebo have been given daily to the patients
with Mild Cognitive Impairment (MCI) for 2 years. At the end of the study, the homocystein
levels in the group taking B vitamins have been found 30% lower than the other group
on placebo. Furthermore, a prominent benefit on global cognition, episodic and semantic

70
memories has been reported in people who were given B vitamins and had avarage basic
homocystein levels over 11.3 mmol/L [49]. However, no positive effect had been reported in
other large placebo-controlled trials that investigated long term use of B vitamins and their
combinations with folic acid [50,51]. Also in a recent study, it’s been shown that folate and
vitamin B12 replacements reduce levels of homocystein but they do not decrease risk of AD
[45]. Therefore adequate evidence related to positive effects of B vitamins on impairment of
cognitive functions are not present yet.
Vitamin D
There are many researches that investigate the association between Vitamin D and risk
of AD on of which antioxidants, antiinflammatory or Aβ formation pathways [52]. Vitamin D
levels in patients with AD has been found lower than in normal individuals [53]. Some trials
showing positive effects of vitamin D replacement on cognitive functions are present [54].
However we need placebo controlled randomised clinical trials in order to learn actual role
of Vitamin D on protection against Alzheimer’s Disease.
Metal Ions
It is thought that zinc, iron and copper have a role in pathogenesis of AD by forming
reactive products in the form of metal amyloid complexes [55]. It is reported there is an
association between zinc deficiency and cognition loss in patients with AD [56]. It has been
shown by in vivo trials that Aβ and tau proteins decline and related memory impairments
are delayed by giving zinc to the rat models [57]. Higher amounts of copper detected in
patients with AD than normal individuals in a meta-analysis corroborates the idea of
the role of copper dysfunction on AD pathology [58,59]. However in a recent prospective,
randomised, placebo controlled trial, it’s been reported that oral copper supplementation
has no effect on cognitive functions in patients with AD [60]. It’s stated that iron is especially
effective on oxidative stress pathways in patients with AD [61,62]. There are some studies
that support iron supplementation to improve attention and concentration [63]. But in the
elderly patients, it is recommended that excessive iron intake by diet should be avoided
[64]. Overall, modulating metals has been proposed as a therapeutic strategy for AD [65].
Bivalent cation chelators (clioquinol) are being developed as a novel AD drug [66].
Fatty Acids
The association between each fatty acid and risk of AD has been investigated by many
epidemiologic and animal studies. Saturated fat is found primarily in dairy products, meats,
and certain oils (coconut and palm oils).Trans fats are found in many snackpastries and
fried foods. Also polyunsaturated fat is found primarily in Mediterranean diet products
such as fish. It is reported that Omega-3 which is a polyunsaturated fatty acid provides
protection against the risk of AD, on the contrary increased saturated fatty acids and
transfatty acids may increase the risk of AD [67-70]. It is predicted especially these positive
effects of omega-3 are via Dacosa Hexaenoic Acid (DHA) and Eicosa Pentaenoic Acid (EPA)
[71,72]. However, in randomised controlled clinical trials have not supported a therapeutic
role for omega-3 fatty acid (with EPA and DHA) supplementation in the treatment of AD
because of data show that they did not slow the rate of cognitive impairment and functional
decline [73-75].
Carbohydrates
It is reported that obese and diabetic individuals have 4 times higher risk of developing
AD, and raised prevalence of obesity and diabetes will increase incidence of AD [14]. Tha
main problem in both obesity and diabetes is insuline resistance. Decreased insulin levels,
insulin receptor expression and insulin resistance have been reported in patients with
AD [76,77]. It is predicted that many proteins in brain neurons become more sensitive
to glycation after excessive glucose exposure, and this may lead to risk of AD [78]. Since

71
an important step in the pathophysiology of the AD is represented by advanced glycation
end products in important plasma proteins concerned with fat, cholesterol, and oxygen
transport, this leads to cholesterol deficiency in neurons, which significantly impairs their
ability to function. Like in many other studies, a diet which is rich in carbohydrates can be
harmful for the patients with AD [79,80]. However, in a large prospective study, it’s been
determined that glycemic load reflexing carbohydrate content in food was not associated
with a higher risk of AD [81]. Although there is no reliable data of the detrimental role of a
diet high in carbohydrate on AD from randomised controlled trials but high caloric diet is
not recommended for AD patients.

The Association between Diet Pattern and Alzheimer’s Disease

There is no defined diet that prevents dementia. A number of diets have been examined
and it is emphasized that Mediterranean diet has more positive effects among them. A
Western diet is characterized by higher intake of red and processed meats, refined grains,
sweets, and desserts [82]. A high-fat Western diet may play a role for development of AD.
There were any available data from epidemiological studies exploring Western diet and the
risk of AD. Traditional Japanese diet is characterized by increased intake of fish and plant
foods such as soybean products, vegetables, and fruits with decreased intake of refined
carbohydrates and meat [83]. This diet pattern was associated with a reduced risk of AD
[84]. A healthy diet is characterized by increased intake of fruits, whole grains, fresh dairy
products, vegetables, breakfast cereal, tea, vegetable fat, nuts, and fish and decreased
intake of meat, poultry, refined grains, animal fat, and processed meat [83]. It was reported
that a healty diet was associated with better cognitive performance and had a positive effect
on the risk of AD [85,86]. The Dietary Approaches to Stop Hypertension (DASH) diet is
characterized by a high consumption of a high intake of plant foods, fruits, vegetables,
fish, poultry, whole grains, low-fat dairy products, and nuts, while minimizing intake of red
meat, sodium, sweets, and sugar-sweetened beverages [83]. In a research on hypertensive,
sedentery, over weigth and/or obese individuals on DASH diet, it has been determined
that neurocognitive functions of ones that follow the diet had a significant improvement
[87]. The Mediterranean diet is characterized by increased intake of cereals, poultry, beans,
nuts, olive oil, fish, fruits, vegetables and bread; a moderate consumption of alcohol; a
lower consumption of red meat and dairy products. A beneficial association between
consumption of Mediterranean diet and AD was shown in many studies [88,89]. Adherence
to the Mediterranean diet may not only affect the risk of AD but also mortality in AD [90].
There is no diet recommendation defined based on available evidence for AD. The
nutrition recommendations to decrease especially the risk of cardiovascular and metabolic
diseases should be considered for prevention and treatment of dementia and AD. In the
light of recent evidence, foods that are rich in omega-3, antioxidants, poly-unsaturated fatty
acids and contain limited simple carbohydrates, in other words a nutrition pattern that
contains fish, vegetable oil, vegetables without starch, fruits with low glycemic index, low
extra sugar and moderate wine consumption should be recommended [91].

Malnutrition in Alzheimer’s Disease

When age-related physiologic changes and risky situations from social aspects (such
as insufficient energy supply, skipping meals, not being able to cook and go shopping, oral
hygiene problems, polypharmacy, social status, comorbid disorders, and being dependent
to another person) overlap with the problems due to AD progression, it may lead to serious
unintentional weight loss and malnutrition [5,92]. When disease progressing, weight loss
and malnutrition which start as impairment of daily living activities in early stages, become
a prominent problem. In a research done by Wolf et al. malnutrition rate in patients with AD
has been determined as 92% [93].
Unintentional weight loss is an importart sign and complain that indicates Protein Energy
Malnutrition (PEM). Approximately 40% of patients with AD has weight loss. In advanced

72
stages of the disease, severity of weight loss increases progressively [92,94,95]. Weight loss
leads to complications (like infections) and more dependency to caregivers. It is reported
that weight loss over 5% in patients with AD is an important risk indicator for mortality [94].
It is stated that malnutrition which occurs as PEM in elderly people affects development
and progression of chronic diseases unfavorably, furthermore it has some causality on
increase in mortality [5,96]. Malnutrition is especially frequent in patients living at home
[97]. Malnutrition develops more commonly in AD patients than normal individuals [98]. It
is reported malnutrition is an indicator of disease progression and unintentionally weight
loss refers rapidly worsening of cognitive function [99,100].
Weight loss begins in the early stages of disease even before diagnosis and it worsens
with disease’s progression. In advanced stage AD, feeding difficulties are present commonly.
Patients forget to eat and go to shopping for cooking, they skip meals and show resistance
to food consumption. And also they may become more sensitive to taste and smell and may
have some chewing, swallowing, and utensils using problems or may aspirate what they eat.
They may be disturbed by noise, lights or crowding during their meal [101]. A seious weight
loss in a patient due to changes in dietary habits may cause feeding with a tube which is
costly and not effective [95].

Approach to Nutritional Problems in Alzheimer’s Disease

Because of lack of appetite in patients with AD, feeding should be provided when the
patient has desire to eat something instead of regular mealtimes. The appetite of the patiets
can be better in early times in a day. That’s why break-fast and lunch should be considered
as more important mealtimes. Most of the patients can need some simple directions to
complete their meals. Eating with hands instead of using utensils should be tolerated [102].
Providing foods patient prefers or likes may increase food consumption [103]. Making simpler
the environment may prevent patient’s distraction during meal. A light music througout
meal may prevent agitation [104]. It is reported that cooking bread or pop corn at mealtimes
increases apetite and food consumption [105].
It is recommended that dietary limitation should be avoided, liquid nutrients should be
given between meals to support energy intake and vitamin-mineral supplements should be
provided. However semi-solid foods should be preferred to liquid ones to avoid aspiration
risk [101].
In every stage AD, apetite of the patient and food consumption at every meal should
be paid attention to prevent malnutrition. If required, consumpted food at meals should
be recorded and counting calories may be done. If malnutrition is determined by tests
performed during clinical follow ups, supplementary nutritional products should be given
in early periods. When choosing a supplementary product, chronic diseases of the patient
should be considered.
When deciding how to feed (with a tube or gastrostomy) the patient in advanced stage of
AD, patient’s values and scientific evidences should be considered altogether. Evidences that
support positive effects of tube-feeding on preventing aspiration, decreasing risk of infection
and extending survival are not sufficient. If long term feeding is considered or patient has
disphagia, healthcare providers should proceed with Percutaneous Endoscopic Gastrostomy
(PEG) as soon as possible. European Society for Parenteral and Enteral Nutrition (ESPEN)
does not recommend tube feeding in patients with terminal AD [106].
A good relationship between patient and caregiver that is responsible for patient’s
nourishment may improve patient’s nutritional status. A helpful, concerned, compassionate
caregiver may succeed to increase food consumption of the patient. Changes in nutritional
habits of patients with AD cause their caregivers to live a stressful, depressed and isolated

73
from social life. Insufficient knowledge of caregivers about nutrition and emotional and
economical burdens affect the healthcare to the patients [95,101,107]. It is reported that stress
in caregivers is related with weight loss defined in AD [95]. Assessment of stress in caregivers
and providing sufficent physchological support may increase life quality of the patient with
AD [35]. Nutrition education programs towards caregivers are considered as best method to
prevent patient’s weight loss, improve nutritional status, and provide sufficient knowledge
about nourishment and stress management [95,108-111]
As the result, incidence of dementia and AD which is most common type of dementia, has
been increasing due to increase in population, prolongation of lifespan, increase in elderly
population. Although there is no special diet to prevent AD, positive effects of Mediterranean
diet that contains omega-3, antioxidants, and foods that are rich in polyunsaturated fatty
acids and includes limited carbohydrates, has been shown. It is very important to follow up
body weight, evaluate the nutritional state in elderly people and inform the relatives about
AD, because decline at body weight in patients may occur before the diagnosis. Nutritional
status evaluation sholud be provided in every stage of the disease. In addition, loss of appetite,
weight loss and disphagia should be determined on time, and nutrition support therapy should
be started immediately. When approaching to the nutritional problems due to aging and AD,
participation of caregivers and relatives should be provided during management.

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 eBooks

Caregiver Education and Support Studies For

Alzheimer’s Disease
*Kahraman Kıral1, Gülgün Uncu2, Demet Özbabalık Adapınar3 and Aynur Özge4*
1
Çağ University, Department of Pscyhology, Yenice-Mersin, Turkey
2
Yunus Emre Government Hospital, Department of Neurology, Eskişehir/Turkey
3
Osmangazi University Department of Neurology, Eskişehir/Turkey
4
Mersin University Medical Faculty Department of Neurology, Mersin /Turkey, Head of
the Turkish Alzheimer Society Mersin Branch

*
Corresponding author: Prof. Dr. Aynur Ozge, Mersin University Medical Faculty
Department of Neurology, Mersin /Turkey, Head of the Turkish Alzheimer Society
Mersin Branch E-mail: aynurozge@gmail.com or aozge@mersin.edu.tr

Abstract
Alzheimer’s Disease (AD) is a degenerative brain disorder in which the societal burden
of this disease is expected to increase over the next 40 years. As the disease progresses,
patients become more irritable and lose their independence in performing activities of daily
living for need a close caregiving. Caregivers of dementia patients are usually known as
informal caregivers. At this step it has to be accepting that caring for a patient with cognitive
and neuropsychiatric impairments is a stressful life event and caregivers carry a heavy
psychological burden. Numerous studies have noted that the problems that mainly affect
the caregiver range from simple physical fatigue, problems with the family and at work,
feelings of incapacity and inadequacy, sleeping difficulties, depression, anxiety, and lower
levels of life satisfaction, especially when compared to non-caregivers. Last 30 years with
the awareness about this issue, social support and caregiver education programs motivated
lots of the area. Positive scientific clues also found that support projects/programs that are
established to provide social support are useful in alleviating caregivers’ distress. The last
10 years have marked a clear shift to a more person-centered, relationship-based model for
caregivers to support optimal wellness in persons with AD. In the next future behavioral
approaches that framed care approaches around caregivers tailoring approaches to match
the person with dementia. This issue will merits more attention not only scientist but also
social workers.

Keywords: Alzheimer’s Disease; Caregiver; Caregivers’ Distress; Social Support; Burden;

Social Cost
Alzheimer’s disease is a degenerative brain disorder characterized by progressive
dementia that culminates in death. It affects 3% of those over the age of 65 and up to 50%
over the age of 85, resulting in a cost of over $100 billion a year in the USA [1]. Due to
the ageing population, the societal burden of this disease is expected to increase over the
next 40 years [2]. The hallmark of Alzheimer’s disease is the insidious onset of memory

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loss, although one or more additional areas of cognitive impairment are usually evident on
examination. Slow but relentless progression leads to worsening cognitive and behavioral
problems, as the result of widespread areas of cortical dysfunction.
As the disease progresses, the cognitive impairments are accompanied by neuropsychiatric
symptoms. Patients become more irritable and lose their independence in performing
activities of daily living. In the later stage, the patient’s loss of independence requires the
presence of a caregiver who can assist with day-to-day tasks. Without caregivers, people
with dementia would have a poorer quality of life and would need institutional care more
quickly, and national economies would be swept away by the advancing demographic tidal
wave. However, this support comes at a cost of caregiver distress and poorer quality of life [2].
Assisting a person affected by cognitive disorders can drain the emotional resources of
any individual so much that the caregiver is often defined as “the hidden patient” due to the
not unlikely possibility of developing mental and physical symptoms. In fact, caregivers end
up dedicating less time to their own needs and to other family and professional roles, thus
neglecting their own personal health and social life [3,4].

Burden among Caregivers of Patients with Alzheimer’s Disease

Caregivers of dementia patients are usually family members, the majority of whom are
female and a child or spouse of the patient [5]. These family caregivers are also known as
informal caregivers. Caring for a patient with cognitive and neuropsychiatric impairments is
a stressful life event and caregivers carry a heavy psychological burden [6,7]. Burden refers
the impact of the illness on the caregiver, and it is a term that expresses the comprehensive
effect on the caregiver’s global needs in the course of looking after the patient (ie, physical,
psychological, and social). Numerous studies have noted that the problems that mainly
affect the caregiver range from simple physical fatigue, problems with the family and at
work, feelings of incapacity and inadequacy, sleeping difficulties, depression, anxiety, and
[8,9] lower levels of life satisfaction [10], especially when compared to non-caregivers [11].
Many of the demands of caregiving may contribute to increase in burden. For example,
caring responsibilities consume large amounts of caregivers’ time and many caregivers are
forced to restrict the time they would otherwise spend with friends and family, or building
social networks, quite often leading to an overall loss of social contacts and jobs [5]. This
deprivation of social interaction causes caregivers to experience feelings of social isolation
[12]. Moreover, caregivers not only encounter the psychological burden associated with
caregiving but also are at an increased risk of developing physical health problems, such as
including cardiovascular problems, lower immunity, poorer immune response to vaccine,
slower wound healing, higher levels of chronic conditions (such as diabetes, arthritis, ulcers,
and anemia), and use of prescription medications, poorer self-rated health, decreased
engagement in preventative health behaviors such as exercise, and greater likelihood of
smoking, drinking alcohol, and poor sleep patterns.. Because of time constraints, caregivers
may not attend to their personal health issues [13].Consequently there are several factors
that contribute to burden of caregivers of patients of AD. For a better discussion we can
summarize them with a number of subtitles.

Patient Related Factors

First symptom of AD is (generally) related to memory dysfunction. However as the time
progressed patients lose their independence and also exhibit neuropsychiatric symptoms.
Neuropsychiatric symptoms and loss of cognitive functions cause behavioral problems and
incontinence. These are the principal patient related factors that predict caregiver burden.
Several studies indicated that there is a strong relationship between caregivers’ burden
and patients’ behavioral problems [14,15]. For example, in their studies Shaji et al., [16]
showed that most frequently identified neuropsychiatric symptoms among their study group

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patients (mostly AD patients) were paranoid and delusional ideations. One another study
found that aggression and wandering also frequently cause caregiver burden [17]. Allegri et
al [18] indicated that there is a strong relationship between caregiver burden and behavioral
disturbances. Specifically, hallucinations, unusual behavior, and abnormal behavior at
nighttime are mostly related to caregiver burden. Some pharmacologic treatment studies
support this situation. There is enough evidence that pharmacological interventions with
cholinesterase inhibitors are efficient in reducing the severity of psychiatric disturbances
in AD. Thus caregivers’ burden tends to decrease after the treatment with cholinesterase
inhibitors [19].Consequently behavioral problems of patients make caregivers to cope with
caregiving demands harder, so they cause to increase the caregiver burden.
Findings about the relationship between patients’ cognitive status, disease stage and
caregivers’ burden are inconsistent. Some findings indicate that there are no relationship
between patient’s cognitive dysfunction and caregiver’s burden (18) whereas other, especially
pharmacological studies, claim that an improvement in patient’s cognitive functions cause
a decrease in caregiver’s burden level [20]. Patient’s diagnoses may affect the caregiver
burden. Caregivers of patients with mild AD reported more sever burden than caregivers of
amnestic Mild Cognitive Impairment (aMCI). Wontedly, the factors that cause the difference
in severity of caregiver burden were neurobehavioral symptoms and daily living activities
[14]. Daily living activities represent patient’s ability in daily functioning and independence.
Thus it is also an important factor that predicts caregivers burden [21,22]. Loss of daily
functioning of a patient create a high level of caregiver-burden because careers have to
waste much of their time to assist patients’ daily function. Caregivers may quit their jobs to
stay at home and take the responsibility of caring for a patient who cannot overcome daily
routines.

Caregiver Related Factors

Caregivers of patients with AD exhibit high levels of burden and depression especially
when compared with caregivers of non-demented patients such as physical disability [23].
Papastavrou et al., [24] found that 68% of AD caregivers reported highly burden and 65%
exhibited depressions. These rates are very high and some factors such as caregivers’ socio-
demographic status and ability to cope with caregiving demand, are also related to caregiver
burden [20,24,26]. To identify this factor may be helpful to alleviate caregiver burden
therefore increase the quality of patient’s life. Because the link between caregiver well-being
and patient’s quality of life is clear [5].
Although there are some inconsistent findings in literature, caregivers’ demographic is
a predictor for burden. There is a relationship between age and burden [27] but how age
influence caregiver burden is not clear. Some findings show that younger age is related to
caregiver burden [28,29] other show advanced age is a stronger risk for caregiver burden
[30]. Previous studies also showed that family caregivers may be motivated to provide care
for several reasons: a sense of love or reciprocity, spiritual fulfillment, a sense of duty,
guilt, social pressures, or in rare instances, greed [31,32]. Daughters-in-law reported more
burden when caring for patients with dementia compared to other caregivers [33,34]. This
can be explained by daughters-in-law tending to perceive looking after their parents-in-
law as a filial obligation [35]. Because daughters-in-law have a consanguinity relationship
with patient and tend to as a role that stems from others’ expectations contributes to
caregiver burden [36]. Ongoing life with AD commonly influence caregiver burden [28]. The
relationship between length of providing care and depression were reported as significant
[36]. Role adaptation which is assumed as an outcome of providing care for a longer period
of time may alleviate caregiver burden. Baseline relationship closeness between patient
and caregiver may predict caregiver burden. There is some evidence that higher baseline
relationship closeness is related to lower caregiver depression [37]. Gender may influence
caregiver burden. Females report higher levels of burden [38,40]. However it is important

82
to note that male caregivers receive support or assistance from their wives. Moreover, they
may regard caregiving as a duty by providing instrumental support [35].
Disagreements about the division of responsibility for care are also a problem and may
cause conflicts between the primary caregiver and other family members, which we assume
to be a secondary source of caregiver burden [40]. Thus, dementia is not only a neurological
syndrome but also a community health problem, especially for developing countries where
more than 60% of patients live and usually receive care in the home [41].
Coping strategies used by caregivers to deal with caregiving stressors may contribute
caregiver burden. A growing body of research suggests that using adaptive coping strategies
provide resilience to caregivers against stress caused by caregiving demand [29,34].
In developing countries, caregivers also face more severe problems. First, family members
do not generally have adequate knowledge of dementia, meaning that an early and timely
diagnosis of the disease is often missed [43]. Caregivers often lack opportunities to receive
social or health services and access to institutions that provide long-term care. Public health
policies that are inadequate require the family caregiver to care for the dementia patient
in the home [16]. However, due to their low or middle-level income, caregivers also have
difficulties in affording care for their patients. Consequently, the psychological morbidity
rates of caregivers are greater in developing countries than in other countries. The 10/66
Dementia Research Group [44] reported that the psychological morbidity rates of dementia
caregivers ranged from 40% to 75% in low or middle-income countries. Consequently
either patient related factors or caregiver related factor influence the burden of caregivers
of patients with AD. These people exhibit higher levels of depression and greater burden.
They lack of awareness and enough information about AD. To alleviate their burden, they
also express need for social support [45]. Thus this will be helpful for caregivers if new
community health policies including providing social support and information to increase
the awareness about AD are developed.

Social Support Requirements

There are a number of ways that social support can be conceptualized. However basically
social support can be defined as a process of providing or exchanging resources to another
person when it is needed [46]. It is very clear that social support contributes to a person’s
ability to cope with stress [26]. On the other hand, a lack of social support leads to feelings
of loneliness, helplessness, and social isolation. A positive relationship between social
support and psychological well-being has generally been found [12]. Support provides a
buffer against burden and stress for caregivers by increasing the perception that resources
are available to handle stress. Previous studies found similar findings for AD caregivers.
Participants reported higher need of social support when they have higher level of caregiver
burden [47] Studies have indicated that social support is useful in reducing caregivers’
burden. For example, support services are perceived as very important by caregivers [48,
49]. Providing respite care is also important because it is helpful for caregivers in coping
with stress [50]. Studies also found that support projects/programs that are established to
provide social support are useful in alleviating caregivers’ distress [51]. There is also a strong
negative relationship between social support and anxiety [8], and caregivers tend to report
increased levels of life satisfaction when they receive the necessary social support [10]. The
main reason why social support is closely related to caregiver burden may be explained
by high demands of caregiving. Caring for a patient with AD is a time consuming process
and may results in changes in the social network of caregivers. However these changes
often result in greater social isolation, less opportunity to engage with others, feelings of
helplessness, and even cognitive decline [13,52]. According to the buffering hypothesis
of social support under some conditions social support protect individuals from negative
outcomes of distress [53]. Thus having higher levels of social support prevents individuals
from feeling helplessness and provides a sense of stability in life situations. When putting

83
these suggestions together, it is not surprising that caregiver tend to seek social support
when they encounter caregiver burden.
The results indicated that social support is an effective variable for reducing feelings of
anxiety and burden. However, it is not always possible for caregivers to find social support.
In high-income countries, public health services may meet the caregivers’ needs of support,
but in middle and low-income countries, the public health system is often inadequate to
meet these needs [11]. However social support is not a unitary concept so it is important
to know the source of support to make more detailed interpretation. Support can be in
several types such as instrumental support (helping with daily living needs and housework),
emotional support, and informational support (information and knowledge from both health
professionals and from those who have experienced similar situations). According to their
needs caregivers may seek these types of support. For example instrumental support
indicates receiving assistance for the basic daily living activities of patients such as eating,
dressing, and bathing. Because caregivers waste a lot of time in providing daily needs of
patients, having instrumental support may allow caregivers more time. Having or lacking
instrumental support also causes some physiological outcomes. In a previous study lower
quality of instrumental support linked to physiological stress [54]. According to the result
of the study caregivers who had lower level of instrumental support showed higher levels
of plasma cortisol. Researchers interpreted this finding as a result of imbalance between
the supply of instrumental support (by other family members) and the perceived need
for it (by caregivers). Actually this is consistent with other expectations which discussed
before and suggested that disagreements about the division of responsibility for care could
cause family members conflict. Type of the assistance is also important to increase the
effectiveness of social support. Formal assistance for instrumental daily activities was found
more associated with decrease in caregiver distress when compared to informal assistance
[55]. On the other hand, when it comes to emotional support caregivers tend to prefer
social workers who have shared experiences with themselves. This means that when
emotional support is offered by social workers who have experience of being family carer,
caregivers most likely accept this offer when compared to other professionals [56]. They
want those who give them emotional support to fully understand the issues about what they
experience. Thus caregivers may benefit from other caregivers’ experience or existence. This
can be seen in a previous study which was carried out by O’Connor et al.,[57]. This study
showed that even caregivers meet with other caregivers in a 3D virtually environment, this
online support groups decreased their distress. Besides instrumental and emotional social
support, caregivers are also concerned about their inadequate income [58] and tend to seek
financial social support [45]. This is consistent with previous studies which indicated that
financial costs associated with informal caregiving were a significant factor in caregiving
burden [59]. Estimated cost of providing care for patients with AD includes not only cost of
providing care but also lost earnings of caregivers. The annual cost of caregiving for per AD
patients was estimated in a ranged from $12,730 to $57,937 [60]. This highly cost reveals
the need for financial social support to caregivers able to maintain appropriate care. Most
of caregivers have inadequate knowledge about the disease. Providing information about
causes and progress of AD, behavioral problems that may encounter or opportunity for
them to use available services can be helpful for caregivers. In their study Rosa et al., [61]
found educational needs of caregivers as “Effective caregiver-to-patient communication”,
“Correct cognitive disorder management” and “Correct behavioral disorder management”.
Besides focusing on caregiving burden, some studies also focus on improving caregivers’
well-being and satisfaction of relationship between caregiver and patient. Carbonneau
et al.,[62] showed that their education program for caregivers has a positive impact on
relationships between patient, caregivers and other family members.
Consequently caring for a patient with AD is highly stressful and exhausted progress,
and caregivers often seek support to decrease their burden and increase well-being. Several

84
support demonstrated showed that any kind of support can be helpful to alleviate caregiving
distress even support is provided by phone call, e-mail or a software that creates virtual
platform [57,63,64]. A crucial part of helping family caregivers is linking them with local
support, best done through local Alzheimer’s Associations. Alzheimer’s Associations provide
information, emotional support, practical advice, support groups, training programs, help
sheets, toll-free helplines, and useful Web sites. They are powerful advocates for people with
dementia and for their families with governments and service providers, as well as funding
research. As these results show educational and social support programs are needed by
caregivers and new policies and services that provide these programs should be established.

Caregiver Education
Dementia care education has come a long way in the last 30 years. It has paralleled
the increase in knowledge about AD itself. In the 1970s, persons experiencing AD were
seen as experiencing a degenerative brain disease that little could be done about. In fact,
the old mantra of clean, dry, and fed was pretty much the Standard of the day. As the “old
culture” of AD care was increasingly challenged, it also became clear that caregivers needed
specialized knowledge and skills to work with persons with dementia.
AD care education initially was an extension of the medical model. Persons who
were “experts” in dementia care were up to date on the most current break through on
neurofibrillary tangles and beta amyloid plaques. Learning that AD was not normal aging or
“senility” was actually a big first step in the history of dementia care.
In the next future behavioral approaches that framed care approaches around caregivers
tailoring approaches to match the person with dementia. During this time we often said that
by using such strategies, we set the stage for good AD care. A variety of simple strategies
(eg, approach gently, make eye contact with the person, smile, go slowly, break down tasks
into component parts) were all care techniques that increased the caregivers’ success in
providing physical care to persons with AD.
The last 10 years have marked a clear shift to a more person-centered, relationship-based
model for caregivers to support optimal wellness in persons with AD. Once the notion that
persons with AD are whole persons and have the right to still be actively engaged in their own
lives became commonly accepted, a great shift began. Now caregivers were seen as crucial
players in the delicate balance of supporting the personhood of those with AD. A number
of principles are central to this model:(1) the person with AD is an individual with value in
his/her own right, (2) to provide excellent care we need to enter into human relationships
with the individual, and (3) that a critical challenge is for caregivers to be willing to see the
world through the eyes of the person with AD. All these principles drive the fabric of the
care relationship. Another important principle that is inherent in person centered dementia
care is the value and well-being of the caregiver. It is becoming an accepted notion that if
the caregiver is not valued, respected, and seen as an essential partner in the relationship of
care, the person with AD is much more at risk for not being seen as a person. Truly person-
centered care is about committing to the dignity and personhood of both the caregiver and
the patient with AD.
Caregivers are integral to quality of life of patients with AD. The high levels of burden and
psychological morbidity are well documented, as are factors that predict which caregivers
are vulnerable to these. Interventions can ameliorate these effects and thereby improve the
quality of the life of patients with AD. The management of the patient with AD requires a
comprehensive plan that includes a partnership between doctors, health care workers, and
families. Caregivers susceptible to negative effects can be identified and could be targeted
for interventions.

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 eBooks

Emerging Therapeutic Approaches

Hakan Yavuzer*
Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine/
1

Geriatrics, Istanbul, Turkey

Corresponding author: Hakan Yavuzer, Istanbul University Cerrahpasa Medical

*

Faculty, Department of Internal Medicine/Geriatrics, Istanbul, Turkey E-mail:

drhakanyavuzer@gmail.com

Abstract
Alzheimer’s disease (AD) is a neurodegenarative disease characterized by proggressive
loss of neurons manifested by loss of cognitive function, daily activity and mood changes.
Pathophysiology of AD is quite complex and currently not fully understood. Even though
widespread synaptic and neuronal loss,Amiloid Beta (Aβ) peptide accumulation at
extracellular senile plaques, intracellular hyperphosphorylated tau proteins are known
many years as histological findings, relationship between AD’s pathopysiology and these
findings are not yet full meaning established. In addition during AD, synaptic changes
and loss, neuronal loss, mitochondrial and oxidative lesions, granulovacuolar degeneration
and apototic changes associated with inflammation are observed. As a consequence of all
these, changes in neurochemicals are also formed. Nowadays drugs used in the treatment
of AD can not prevent the occurrence and progression of the disease. By treatment the
symptoms of disease disappear and/or severity of the disease decreases. In recent years,
many experimental studies built on Aβ, taupathy and the neurotransmitter system are able
to come to the stage of clinical trials. Beside these, researches continue on new mechanisms
such as oxidative stress, inflammation, mitochondrial dysfunction, lack of neurotrophin,
caspase inhibitors and sirtuins which are thought to be involved in the pathophysiology
of AD. It is hoped that results of intensive researches on new therapeutic approaches will
provide significant improvements for the treatment of disease in the near future.

Keywords: Alzheimer’s Disease; Therapeutic Approaches

Introductıon
Alzheimer’s disease (AD) is a neurodegenarative disease characterized by proggressive
loss of neurons manifested by loss of cognitive function, daily activity and mood changes.
Pathophysiology of AD is quite complex and currently not fully understood. Even though
widespread synaptic and neuronal loss, Amiloid Beta (Aβ) peptide accumulation at
extracellular senile plaques, intracellular hyperphosphorylated tau proteins are known
many years as histological findings, relationship between AD’s pathopysiology and these
findings are not yet full meaning established. In addition during AD synaptic changes and
loss, neuronal loss, mitochondrial and oxidative lesions, granulovacuolar degeneration

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and apototic changes associated with inflammation are observed. As a consequence of
all these events, changes in neurochemicals (cholinergic, serotonergic, noradrenergic,
dopaminergic decline and glutamate toxicity) are also formed. Acethylcholine (Ach) is a
neurotransmitter which binds hippocampus to cerebral cortex. In AD, earliest and main
patholgy is impairment of cholinergic system in the brain, particularly in areas associated
with learning and memory [1]. The loss in cholinergic neurons are associated with Aβ and
tau pathologies.
In recent years glutamate toxicity is also considered on AD’s pathogenesis. Glutamate
is the main excitatory neurotransmitter in the brain. Glutamate rising by post-synaptic
N-Methyl D-Aspartate (NMDA) receptor activation, activates the voltage-gated calcium
channels and it leads to the influx of calcium into the cell and it faciliates apoptosis.
Furthermore glutamate induces formation of senile plaques an neurofibrillary tangles [2].
Nowadays drugs used in the treatment of AD can not prevent the occurrence and
progression of the disease. By treatment the symptoms of disease disappear and/or severity
of the disease decreases. Treatment must not only treat the symptoms of the disease, but
also prevent the formation of neurofibrillary tangles, amiloid plaques and inhibit neuronal
degeneration. Today, in order to stop amyloid peptid secretion, aggregation and tau
hyperphosphorylation many of the drug or agent are under clinical trial stage. Promising
drugs which is being used today and has reached the clinical trial stage will be reviwed here.

Therapeutıc Targets Focusıng On Amyloıd Beta Cascade Hypothesis

Inhibition of Amiloid Beta Production
Neuronal plaques spesific for AD are composed of Aβ proteins. Aβ is a fragment of the
larger transmembrane protein that its function is not completely understood (Amiloid
Precursor Protein [APP]) by proteolytic pathways. APP metabolised by cutting a series of
proteloytic enzymes (α, β and γ secretase). α-secretase cuts the APP aproximately midline
of Aβ, it constitutes a soluble protein which is participating in the structure of neuronal
cell wall. However if APP is cleaved by other two enzymes from the amino terminus by
β-secretase or from the carboxy terminus by γ-secretase, the product is Aβ. The Aβs are
composed of 40 or 42 amino acids in length. 42 amino acid form which is more amyloidogenic
collapses forming first aggregation [3]. After aggregation of Aβ into diffuse plaques, it turns
into dense neuritic plaques. After the formation of neuritic plaques, inflammation, apoptosis
and excitotoxicity occur; this is a secondary cascade possibly associated with apoptosis-
mediated additional damage. Drug treatment strategies which are being developed in this
field, are focused on increasing the α - secretase activity, β-secretase inhibitors and gamma
secretase inhibitors and modulators.
Alpha Secretase Activator
A metalloprotease type enzyme, α-secretase, which is a member of the ADAM (A
Desintegrin And Metalloproteases) family is a nootropic and neuroprotective enzyme that is
important for neuronal development. Aβ formation is inhibited when the enzymatic cleavage
of APP occurs by the α-Secretase. Therefore, α-Secretase activators are thought to be useful
for treatment of AD.
Due to the similarities with Tumor Necrosis Factors (TNF) it is also called TNF Converting
Enzyme (TACE). α-secretase can be induced by Protein Kinase C (PKC) activators such
as phorbol ester. The drugs stimulating the receptors that act through PKC, muscarinic
agonists, statins, steroid hormones (oestrogens, testosterone), and nonsteroidal anti-
inflammatory drugs may increase the activity of α-secretase.
At mild to moderate AD, Etazolat (EHT-0202) that is a selective receptor modulator has
completed phase 2 studies [4,5]. Bryostatin-1 which is a macro cyclic lactone provides

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α-secretase activation via PKC activation. Phase 2 studies of Bryostatin-1 are ongoing [6].
Exebryl-1 leads to a significant reduction of Aβ peptid production and accumulation in
mouse brain. It is able to improve memory by regulation of α and β secretase activities [7].
Beta Secretase (BACE1) Inhibitor
β-secretase is a pepsin structured aspartilprotease which is found at golgi apparatus,
endosome and in the cell membrane part. β-secretase is also called β-APP-Converting Enzyme
(BACE). Beta-site APP-Cleaving Enzyme 1 (BACE-1) which is encoded on chromosome 11 is
effective in Aβ production. Inhibition of BACE-1 reduces Aβ production.
In initial studies, quite potent β-secretase inhibition by two substances called OM99-1
and OM99-2 were shown. β-secretase enzyme inhibitors have also been found to increase
the Aβ clerance in transgenic mouse models. Membrane transition state of these molecules
is weak, in order to cross the blood brain barrier and achieve an effective level on the central
nervous system, studies are ongoing [8].
After these molecules CTS-21166 exceeded to phase I clinical trials by reduction brain
levels of Aβ over 35%, and 40% reduction of plaque burden. It has been shown that the
drug can be well tolerated in healthy volunteers and effectively reduce the plasma Aβ levels
[9]. However, studies on MK-8931 which has very good oral bioavailability are progressing
with the phase 3 studies [10]. In mouse models promising β-secretase inhibitors which has
completed by other researches are KMU-429, 188 909 and GRL-8234 GSK.
Gamma Secretase Inhibitors and Modulators
The enzyme γ-Secretase which contains presenilin is a complex transmembrane protein.
This enzyme consists of 4 parts which are presenilin-1 and 2, the nicastrin, presenilin
enchancer 2 (PEN-2) and anterior pharynx-defective phenotype-1 (APH-1) [11]. The enzyme
γ-Secretase is necessary for many physiological secondary signaling pathways and also
synthesizes Aβ42 protein. Therefore, γ-secretase inhibitors, has been the subject of study
for the treatment of Alzheimer’s disease.
DAPT is the first dipeptide compound having the γ-secretase inhibitor activity in vivo
tests. It inhibits Aβ production in cells. However, it has been shown that high doses are
needed to reduce of the Aβ levels in young APP transgenic mice brain [12].
Despite being bioavailable and brain-penetrant, toxicities associated with γ-secretase
inhibitors hinder the development of therapeutic approaches targeting γ-secretase. The
most commonly reported side effects of γ-secretase inhibitors are hematological and
gastrointestinal toxicity, skin reactions and hair color changes [13-17]. Although LY-450139
and Semagacestat significantly decreased Aβ plasma levels in clinical studies, they were
shown to impair cognitive function, increase skin cancer and infection risk and so they have
been cut [18,19].
To overcome the above-mentioned toxicity problems, the notch sparing second generation
of γ-secretase inhibitors has been developed. Avagacestat (BMS-708163), Begacestat (GSI-
953) and NIC5-15 clinical studies has been initiated. Avagacestat phase 2 trials have been
ended due to the absence of a positive effect on cognitive function compared to placebo, and
gastrointestinal and dermatological system adverse effects [20]. A natural monosaccharide,
NIC5-15, that is in the phase 2 study phase, has shown good tolerance and safety [21,22].
Promising results of Begacestat phase 1 studies are under clinical evaluation for the
treatment of AD.
Anti Beta Amyloid Aggregation
Arresting of the accumulation or aggregation of abnormal Aβ’s at the fibrils and oligomers
prevents the formation of neuritic plaques. While Aβ fibrils and Aβ oligomers showed toxic

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effects in cell cultures Aβ monomers does not show toxic effects. Aβ fibril formation resembles
crystallization formation [23,24]. Aβ’s can not stay stable on some critical concentration and
precipitate [25]. This level of critical concentration may vary depending on Aβ’s type and
on environmental conditions. For example, Aβ42 tends to create more fibrils compared
to Aβ40. The level of concentration required for the generation of fibrils is lower for Aβ42
compared to Aβ40 [26]. Aβ fragments which are synthesized and released from cultured
cells show negative effects on learning and memory by disrupting synaptic plasticity in the
the synaptic links [27]. Certain compounds which prevents blocking of the fibril formation
and Aβ collapse such as cholyl amide PPI 368, D-peptid PPI 1019 and L-peptid iAβ5p may
contribute to treatment of Alzheimer’s disease. However, the effects of these compounds
have been demonstrated only in vitro. There is no in vivo effects because they degradate in
the plasma. This is the most important reason that prevents the clinical practices [28].
Studies in recent years have focused on three strategies to prevent the Aβ aggregation:
anti aggregate compounds, metal complexing agents and immunization.
Nonpeptidic Antiaggregates
The first representative of this group is derived from propionic acid, tramiprosate. Phase
3 studies conducted with this drug was stopped due to low penetration to Central Nervous
System (CNS) and poor potential [29,30].
Scyllo-inositol, one of the second generation drugs, is considered to have an effect to
prevent Aβ aggregation and accelerate dissociation of aggregates. Inositol content of drug
can help overcome the blood-brain barrier after peripheral administration and it can
access the CNS in high concentrations. Phase 2 studies continues in mild-to-moderate
Alzheimer’s patients [31]. Epigallocatechin-3-Gallate (EGCg), a polyphenol from green tea,
has been shown to stimulate the alpha secretase activity in animal models and to inhibit
Aβ aggregation. It has also multiple functions such as modulation of cell transmission,
regulation of cell survival/death, and protection of mitochondrial function. Therefore, phase
3 trials for AD therapy is ongoing [32].
Metal Complexing Agents
In older ages metal ions such as copper, aluminum, iron and zinc concentrates more on
the brain [33]. In AD, abnormal increase of metal ions in the neocortex may have an initiator
role in increased formation of neurotic plaque due to Aβ42 [34,35]. In addition, detection of
metal ions such as copper, zinc, and iron on Aβ plaque structure has led to the view that
metal chelation treatment may be effective for AD [36]. Clioquinol (PBT2), an antibiotic,
targets Aβ reactions with synaptic Zn and Cu. It has a powerful central nervous system
permeability. It is proven to decrease Aβ42 concentration in the cerebrospinal fluid (CSF)
and improve cognitive and behavioral performance; the phase 2 studies ha been completed
[37].

Immunization
Utilization of the immune system has been thought to find a solution for the main Aβ
problem in the AD pathophysiology. Therefore, immunization has been tried as a therapeutic
strategy of the disease. Abnormal immune response that damages tissue can be changed
by forming various immune responses to stop pathological events in the tissue [38]. As
the most striking example, it has been markedly demonstrated that after immunization
with Aβ therapeutic effects were observed in transgenic mice model of Alzheimer’s disease
[39,40]. Immunization created a secondary immune response against previously formed Aβ
accumulation in the brain by stimulating inflammatory responses such as microgliyosis,
astrosis, complement activation, formation and releasing of cytokines and acute phase
proteins. In the first animal study, inhibited amyloid formation, reduced plaque formation
and imporoved cognitive function were observed in genetically amyloid producing transgenic

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mice by vaccination with peptide [40,41]. This process is made by (i) administration of
peptides of Aβ itself or different parts of Aβ, as active immunization (ii) administration of
antibodies generated against to the Aβ, as passive immunization [39,40].
Active Immunization
AN-1792 was the first human antigen Aβ1-42 tested in mice and leading to produce
quick and large amounts of antibody that attaches to Aβ in the CNS. Phagocytosis took
place with the activation of microglias. But because of aseptic meningoencephalitis and
cerebral microhemorrhages occurred during studies, phase 2 studies were stopped. The
formation of these complications has been linked to autoimmune responses and cytotoxic
T cells [42,43].
After that, the vaccines without T cell epitopes were produced. Lately, phase 2 trials of
CAD 106 which contains peptides of Aβ1-6 in mild AD have been completed. Molecule has
been shown to not lead to meningoencephalitis [44]. UB 311 contains B cell epitopes (Aβ
1-14) and V950 (Aβ N-terminal conjugated to ISCO-MATRIX) are two promising vaccines
their phase 1 trials are done. Recently, related studies with AD-01 and AD-02 which are
targeting the Aβ N-terminal fragment are underway [45].
Passive Immunization
Another way to inhibit the immune response is the to apply antibody directly. Although
no change was determined in Aβ plaques, a rapid improvement in cognitive functions was
observed in mice after the administration of monoclonal Aβ antibodies. Two basic action
mechanisms take play in this improvement. The first is cleaning of antige-antibody complex
from locally activated microglial cells and increase in complex clerance. The second result of
binding of Aβ with Aβ antibodies is to increase the solubility of Aβ and removal from plaque
in the brain [47]. In summary, it is possible to remove amyloid plaques, save neuritic and
glialfunction, reduce early tau hyperphosphorylation and cytopathology and to reverse the
abnormal hippocampal synaptic plasticity by passive immunization [48-50].
Since therapeutic effect of Bapineuzumab (AAB-001) on cognitive or functional outcomes
was not detected in patients with mild AD, the phase 3 studies were terminated [51]. Phase
3 studies of Solanezumab (LY2062430) and Gantenerumab in patients with mild AD are
ongoing. Phase 2 studies of a new humanized antibody Crenezumab, which has a IgG4
backbone are continuing.
Tau
Backbone of Neurofibrillary Tangles (NFT) are the hyperphosphorylated tau proteins.
Tau is bound to microtubules and plays important role in microtubule stabilization,
cytoskeleton integrity and axonal transport. In the pathogenesis of AD, hyperactive kinases
and/or hypoactive phosphatases lead to hyperphosphoylation of tau protein, which in turn
disrupts the ability of binding to microtubules. The unbound hyperphosphorylated tau
forms insoluble double stranded polymerizable filaments. In time it becomes intraneuronal
NFT. NFT eventually cause cell death by disrupting the integrity of the cytoskeleton and
axonal transport [52]. Studies have been conducted on kinase inhibitors and inhibition of
Tau aggregation for treatment of AD.
Kinase Inhibitors
Protein kinases play a central role in regulation of many mutually cell functions and
guarantee the normal physiological state. However, Glycogen Synthase Kinase 3 Beta
(GSK3β) and Cyclin dependent kinase 5 (CDK5) are the responsible enzymes in tau
hyperphosphorylation. If these kinases are inhibited, Aβ accumulation can be prevented.
First class Tau inhibitors are intended to regulate the Tau’s phosphorylation by
reducing associated kinase activity. Because deteriorated relationship between glycogen

93
syntase kinase 3 beta (GSK3β) and protein phosphatase 2A (PP2A) increases the Tau
hyperphosphorylation and intracellular NFT formation [53].
Lithium and valproate have been shown to prevent taupathy by inhibiting GSK3β in
animal studies. However, in clinical studies in AD patients it has not been proven that they
provide enough improvement on cognitive function [54,55]. Preclinical studies conducted
with GSK3β inhibitor derivative molecules such as paullone, indirubin, and maleimide
families came to dead end because of severe cytotoxic effects.
Another important kinase is CDK5 that causes tau pathology by taking part in Tau
phosphoylation. It has been shown that CDK5-selective inhibitors reduce levels of Aβ in
preclinical studies [56].
Inhibition of Tau Aggregation
Another therapeutic approach is to prevent fibrillation of tau and provide the dissolution
of fibrillated tau proteins. In the studies, methylene blue (Metiltioninium) was successful in
completing the phase 2 trial [57,58]. TRx0237 is another methylene blue which has a better
bioavailability. It has been shown to provide a better spatial learning in animal studies [59].
Nicotinamide, the precursor of coenzyme Nicotinamide adenine dinucleotide (NAD+), was
shown to prevent phosphorylation of tau in mice. In mild-to-moderate Alzheimer’s disease
phase 2 studies are ongoing.
Epothilone D (BMS-241027) is an agent that inhibits tau aggregation by microtubule
stabilization. It has improved behavioral and cognitive loss, inhibited the loss of neurons
and limited the taupathy in animal models . Currently phase 1 clinical trials are ongoing
[60].

Therapeutıc Targets Focusıng On Neurotransmıtter System

In AD, earliest and main patholgy is impairment of cholinergic system in brain,
particularly in areas associated with learning and memory. The loss in cholinergic neurons is
associated with Aβ and tau pathologies. In recent years glutamate toxicity is also considered
on pathogenesis of AD. Glutamate is the main excitatory neurotransmitter in the brain.
Glutamate rising by post-synaptic NMDA receptor activation, activates the voltage-gated
calcium channels and leads to the influx of calcium into the cell and thus faciliates apoptosis.
Furthermore glutamate induces formation of senile plaques an neurofibrillary tangles.
Today, the most basic approach for AD therapy is to improve cholinergic neurotransmission
in the brain. For this purpose, addition of acetylcholine precursors, acetylcholinesterase
inhibitors (to reduce the degradation of acetylcholine), nicotinic and muscarinic receptor
agonist and other drugs with cholinomimetic activity are used. Cholinesterase inhibitor
drugs donepezil, galantamine and rivastigmin are the currently available treatments for the
symptomatic treatment of AD. However, these drugs have a short half-life, their effect is
temporary and poor, the therapeutic window is narrow, and also in clinical use, they have
frequent and sometimes severe side effects. All these factors limit their usage in therapy.
In order to develop drug with higher safety and effectivity intensive researches are ongoing.
Recent investigations have focused on the development of novel acetylcholinesterase
inhibitors.
Natural based acetylcholinesterase inhibitors consisting of alkaloids are some alternative
medicines and herbs. These compounds, huperzine A and huperzine B, are composed of
berberine and their semisynthetic derivatives [61].
In addition, some drugs as synthetic acetylcholinesterase inhibitors group are tacrine
based dimers and hybrids. In this field studies on agents such as tacrine-donepezil
hybrids, tacrine-indole hybrids, tacrine-huprine Y hybrids, tacripyrines, tacrine-ferulicacid

94
and tacrine-caffeic acid are continuing [61]. These agents take play role in both the
acetylcholinesterase inhibition and in other activities associated with AD. Thus, while
increasing cognitive function, they may be effective treatment options in preventing and
slowing neurodegeneration.
Another neurotransmitter that is indirectly involved in neuronal degeneration and
memory loss is serotonin. It has been shown that increasing the release of Ach and
cholinergic transmission by inhibition of 5-HT6 (5-hydroxytryptamine 6) has positive effects
on memory and learning disorders. In studies, the effect of 5-HT6 antagonists on protection
from anticholinergic drug induced amnesia has been reported [62]. Recently serotonin
antagonists, PRX-03140 (5-HT4 antagonist) and SB-742 457 (5-HT6 antagonist), have
completed phase 2 studies. Lu AE58054 (5-HT6 antagonist) is ongoing phase 3 studies.

Possıbly Ad Assocıated Other Treatment Approaches

As mentioned above, therapeutic approaches targeting Aβ cascade and neurotransmitter
system are not providing distinct solutions and led investigations on other mechanisms.
The most well knowns are oxidative stress, inflammation, mitochondrial dysfunction, lack
of neurotrophin, caspase inhibitors and sirtuins. This new many therapeutic potential
associated drugs are under clinical investigation.
Neurotrophin
A protein which is secreted from neurons, Nerve Growth Factor (NGF), is necessary for
the neuron development and maintenance of neuron life. It has been shown to prevent
neuronal death in neurodegenerative diseases like AD [63]. Due to problems in crossing
the blood brain barrier, NGF has searched for new molecules and began work on CERE-
110 (Adeno-associated virus-based gene delivery vector expressing human nerve growth
factor). Injection of CERE-110 to direct brain associated Phase 2 studies are ongoing [64].
Cerebrolysin has been shown to improve cognition and daily living activities in mild to
moderate AD [65].
Caspases Inhibitors
Cysteine ​​aspartyl proteases (caspases) that accelerate the apoptotic cascade have a role
in the pathophysiology of AD. Increasing evidence has shown that, as an early event in AD,
Aβ accumulation induces caspase activation so that causes caspase-induced fragmentation
of tau. Tau cleavage seems like a critical event in the formation of NFT, thus caspase
inhibitors, Z-VAD-FMK, Q-VD-OPh and Minocycline, were developed. Of these, minocycline,
acts by inhibiting caspase 3 activation. Minocycline which has oral use with dual function
as both anti-apoptotic and anti-inflammatory may be helpful in treatment of AD [66].
Sirtuins
Sirtuins (SIRT) are NAD+ - dependent protein deacetylases. Seven sirtuin isoforms (SIRT1-
7), which are differ in their highly conserved central NAD+ binding and catalytic domain,
have been described in humans. Each enzyme presents a distinct biological activity role, due
to their substrate specificities, subcellular localization and expression patterns [67]. There
is an increasing data on the physiological functions of sirtuins and their involvement in
disease-related mechanisms. Some of these mechanisms are oxidative stress, inflammation,
cell-cycle regulation, and insulin secretion. Sirtuins have been associated with age-related
disorders such as cardiovascular disease, cancer, metabolic disease and neurodegenerative
disorders and also aging process [68].
The biological function of sirtuins are mainly related to the type of substrates they act
upon, which can be categorized in three main groups: transcriptional regulating, metabolic
regulating and apoptosis regulating.

95
 In many studies, it was shown that sirtuins play important role in neurodegenerative
diseases. SIRT1 has a positive effect in axonal protection from damage in an animal model
of Parkinson disease. Additionally, SIRT1 overexpression protects from Alzheimer’s disease.
Some studies have demonstrated that SIRT1 overexpression reduces Aβ production and the
formation of plaques in mice brain. SIRT1 may be a new theuropeutic molecule in learning
and memory skills by activating the gene for brain derived neurotrophic factor [69].
It is known that the overexpression of SIRT2 can extend organism lifespan and is
often correlated to caloric restriction since many years ago. But this association is still
unclear. Studies in mice showed that SIRT2 inhibition increased acetylated tubulin,
reduced hyperphosphorylated tau protein and restored cognition in AD transgenic mice.
Additionally, SIRT2 inhibition displayed in vitro and in vivo neuroprotective effects in
models of Parkinson’s and Huntington’s diseas [70]. Furthermore, SIRT2 has been shown
to accumulate in the aging brain [71].
Among human sirtuins, SIRT1 and SIRT2 remain the most studied and also best known
to date. Many sirtuin inhibitors have beeen proposed for therapy against neurodegenerative
diseases. In recent studies a number of sirtuin inhibitors have been discovered and reported.
Some of their specific inhibitors have been proposed such as AGK2, salermide, splitomicin,
sirtinol, EX-527, AK-7, cambinol and suramin.
There is solid evidence showing the association of SIRT2 to neurodegeneration and
neurodegenerative diseases. AGK2 is the most known potent inhibitor of SIRT2 with an
estimated IC50 (Half maximal inhibitory concentration) of 3.5 µM, representing a significant
increase over the low selective SIRT2 inhibitors like EX-527 and salermide [72,73]. It also
inhibits SIRT1 and SIRT3 when its concentration is over 40 µM. The protective role against
dopaminergic cell death of AGK2 was demonstrated in Parkinson’s disease [72]. AK-7
exhibits in vitro SIRT2 selective inhibitory activity [74]. In cultured neuronal cells and brain
of mice, AK-7 was shown to reduce cholesterol biosynthesis and total cholesterol level in
primary striatal neurons by inhibiting SIRT2.The effects on cholesterol homeostasis suggest
that it can be used AD treatment in the future [75]. In recent years, extensive research with
SIRT inhibitors gives hope for the future treatment of neurodegenerative diseases such as AD.
With better understanding of reasons of Alzheimer’s diseases pathology, new treatment
strategies will be developed, and new drugs which has less and more tolerable side effects
will be used in the treatment. Especially in recent years, many experimental studies are
built on Aβ, taupathy and the neurotransmitter system that were able to come to the stage of
clinical trials. Beside these, researches continue on new mechanisms which are thought to
be involved in pathophysiology of AD such as oxidative stress, inflammation, mitochondrial
dysfunction, lack of neurotrophin, caspase inhibitors and sirtuins. It is hoped that results of
intensive researches on new therapeutic approaches will provide significant improvements
for the treatment of disease in the near future.

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 eBooks

Future Perspectıve
*Aynur Özge1, Nevra Öksüz and Osman Özgür Yalın3
1
Mersin University Department of Neurology, Mersin, Turkey; Head of the Turkish
Alzheimer Society Mersin Branch
2
Samandağı Government Hospital, Neurology Department, Hatay, Turkey
3
Istanbul Education and Research Hospital, Neurology Department, İstanbul, Turkey

Corresponding author: Mersin University Department of Neurology, Mersin, Turkey;

*

Head of the Turkish Alzheimer Society Mersin Branch Prof. Dr. Aynur Ozge (MD)
E-mail: aynurozge@gmail.com or aozge@mersin.edu.tr

Abstract
Increasing prevalence and incidence of Alzheimer’s disease pointed the groving
importance of protection studies. An early detection of the onset of neurodegeneration in
AD is vital. It can provide a chance for an early treatment that may be helpful to prevent
progression of the disease. Diagnosis of AD is based on neuropsychological tests and
clinical consideration. However chemical, genetic, and neuroimaging biomarkers are
also growing as main components of the exact diagnosis. Current managements of AD
compromise the cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the
N-Methy-D-Aspartate (NMDA) antagonist memantine for AD. However, in the next future
disease-modifying drugs can be available for AD sufferers. Also additional social support
and protection studies will provide additional information to routine clinical practice. At this
section we will discuss ongoing clinical and experimental research and discuss near future
expectations with the ligh of current evidence.

Keywords: Alzheimer’s Disease; Biomarker, Cholinesterase Inhibitors; Disease-Modifying

Drugs; Memantine; Sysmptomatic Management;

Clinical Aspects
About 5 million new cases are occuring every year with dementia, most suffering from
Alzheimer’s disease. In AD the years lived with disability is more than other disorders. The
rapid increase in the number of patients will result with great economical and social burden.
Except well-known etiological factors including older age and limited genetic factors, exact
etiological factors are undetermined. In addition to these factors, it is shown that disorders
which causes vascular risk factors as smoking, high blood pressure, obesity, diabetes,
and cerebrovascular lesions have prominent impact on dementia. And also psychosocial
and educational factors including high education years, active social life, physical exercise
and mentally stimulating activity have possible benefits in the pathogenetic process of the
dementing disorders. According to US Disease Control and Prevention Centers the number
of people over 65 years in the world is expected to be increased from 7% to 12% [1,2], and

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AD prevelance will increase exponentially, especially in developing countries. There are still
unknown parametres related with AD epidemiology and we need to broad-population based
research especially for middle and low-income countries.
There are three mutations established resulting to autosomal dominantly herited AD
including, presenilin-1, presenilin-2 and amyloid precursor protein, these familial AD
patients consitutes only 2-5 per cent of AD population [3] The remaining patients establish
sporadic AD and have a complicated, heterogeneous pathophysiological process. Vascular
pathway related gene mutations should be investigated at the future because of established
effects of vascular risk factors at AD development. Vascular hypothesis is an established
important risk factor at dementia. Smoking, alcohol abuse, obesity, hypertension,
hyperlipidemia, nutritional factors, diabetes mellitus, ischemic heart and cerebral diseases
are investigated areas of research.

Nutritional Considerations
The role of nutritional and dietary factors is controversial. Studies about dietary factors
are insufficient and limited. Many follow-up studies have shown the benefits of antioxidants
like vitamins E, C and mediterranean diet but also there are negative reports. B12 and folate
supplementations have no benefits on cogniton but by reducing serum homocysteine level
may have benefits. It has been reported that using saturated fats and cholesterol in diet
increases the risk of AD, whereas polyunsaturated fatty acids may be protective. Fatty
acids take a part in the synthesis of nerve cell membranes and necessary for synaptic
plasticity and neuronal degeneration. Supplementation of antioxidants or diet which
includes antioxidants such as vitamins E and C may prevent AD [4]. A long-term direct
effect of uncontrolled hyperglycemia, hyperinsulinemia or impaired insulin response on
neurodegenerative changes in the brain has shown. We believe in that, there is no rational to
assume whole metabolic syndrome components as risk factors for AD. To recognize diabetes
mellitus and hyperinsulinemia as risk factors of disease seperately seems more rational.

Psychosocial Factors
A systematic review found that psychosocial factors and actively social lifestyle may
reduce the risk of AD and dementia. An association of low education with an increased
risk of dementia and AD has been reported in numerous studies. Education provides
neural and cognitive reserve to cope with degenerative pathological changes in the brain
and delay onset of the dementia. The risk for dementia and AD was also increased in older
people with increasing social isolation and less frequent contacts with relatives. Poor social
network is associated with cognitive decline. Rich and large social networks also influence
cognitive function and different health outcomes through behavioral, psychological, and
physiological pathways [5]. Mental activities including social activities, watching specific
tv shows, dancing, playing musical instruments has protective effect in AD and dementia.
Many studies showed that high complexity of work with people might reduce the risk of AD
due to reducing rate of hippocampal atrophy [4].
We do not have enough information about toxic or inflammatory factors due to
insufficient and limited studies. Heavy metals such as aluminum and mercury have been
investigated as a risk factor for AD, and even taken of aluminum from drinking water may
be a risk factor for AD. However, this is not confirmed yet. A higher level of C-Reactive
Protein (CRP), interleukin-6 showed an association of increased incidence of dementia
and AD. Also Non-streroidal Anti-Inflammatory Drugs (NSAIDs) may have beneficial effect
against AD and dementia. Neuritic plaques in the brain are associated with inflammatory
proteins. Therefore inflammatory mechanisms that cause neurodegeneration should be
more searched. Neuropathological studies did not find association between use of NSAIDs
and AD’s pathological changes. But we need more studies for getting more information to
prevent dementia and AD [6].

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Diagnosis and Definitions
The most commonly used diagnostic criterias of AD and recently developed new
diagnostic criterias (IWG and NIA-AA) and DSM-V published at 2013 were discussed on
previous chapters. At this chapter we will discuss promising evident and will discuss how
these studies could change disease course at the near future. Neuropsychological tests need
a compherensive interview with the patient, including assessment of attention, behaviour,
memory, language and personality. But it has shown that these behavioral tests may give
false negative results for patients with mild symptoms.
Biomarkers are substances that are used as an indicator of a biological state, most
commonly of a disease. Biomarkers are considered promising in early diagnosis. A good
biomarker should differentiate different diseases and diseased tissues from healty ones.
There are two kinds of biomarkers including genetic biomarkers and biochemical markers24.
Biochemical markers base on pathology of AD. Contemporarily the wellknown biochemical
markers of AD are tau protein and Aβ level in CSF.
PET molecular imaging leads for diagnosing AD. As a result of 18F-FDG-PET, binding
to Aβ40 fibrils were discovered. 18F-FDG-PET has approximately the sensivity of 91%.
18
F-FDG-PET crosses the blood-brain barrier and can determine the localization of NFT and
senil amyloid plaques. Combining PET with other biomarkers and SPECT, provides a new
pathway to early diagnosis [7].
MicroRNAs (miRNAs) comprise 1% of all human genes and play role in the pathogenesis of
neurodegeneration and can be used as a signature for neurodegenerative conditions. miRNAs
are especially found in high amounts in nervous system. Exosomes which are secreted by
many cell types including vascular endothelium involved in neurological disorders, ease
the transportation of miRNAs. Exosomes have significant potential as biomarkers because
of their acquirement easily from blood and urine due to their constitution. The advantage
of using miRNAs as biomarkers is easily detection with specifity and well preservation in
formalin and also in fresh snap-frozen specimens [8]. There are subgroups of miRNAs family
and all these groups have sensivity and specifity at 79-100% and 79-95%. Elevated tau
phosphorylated in exomes obtained from CSF of AD with mild symptoms were detected which
are normally present in accumulated exosomal amyloid peptides in the brain plaques. There
are recent studies about plasma phospholipids levels which we hope to use as prediction if
the normal individual will develop MCI or AD.

Genetic, Where To Go?

In addition to identification of three casual genes and APOE in AD, identification of
CLU, CR1 and PICALM as novel risk genes in late-onset AD is promising. We need more
detailed GWA meta-analyses to detect new risk genes with smaller effect sizes. But we need
large population based studies to find undetected genes. On the other hand including only
isolated populations may reduce the genetic heterogeneity and possibility to find undetected
genes.
GWA studies are insufficient to detect rare variants for now. New detection methods
allow screeining the complete allelic spectrum of AD in large AD populations. With the
reducing costs of novel technologies, future GWA studies may include rare variants to
provide associations of genetic variants in AD, which play an unknown role. Also genome
studies might provide extensive re-sequencing methods to search different locuses in
different chromosomes. No single method will explain the genetic spectrum of AD, more
extensive approaches are recommended. The main issue over the next years will be about
methods in the integration of analyses [9].
Complex diseases as AD are caused by a limited number of common variants with small
predisposing effects. Contemporarily role of environmental and genetic factors are not well-

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defined up to now. Although genetic searches are complicated, promising strategies are
being developed to optimize comprehensive approaches thus will provide us genetic risk
profiles to improve medical healthcare [10].

Therapeutic Approaches
Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic
factor enhancers, and stem cell-related approaches are also under investigation [11,12].
Antiamyloid approaches
Aβ peptide cleavage from APP is catalyzed by fist β- and then γ-secretase. This is called
amyloidogenic pathway, which results with production of less toxic Aβ38-40 about 95% or more
toxic Aβ42 less than 5%. In the nonamyloidogenic pathway, APP is first cleaved by α-secretase,
then by γ-secretase to originate a smaller C-terminal fragment. Nonamyloidogenic pathway
precludes Aβ42 formation and in fact it is the predominant pathway for amyloid metabolism.
Genetic and environmental factors may change this balance and increase production of
toxic Aβ42 peptide [13].
Both use of β- and γ-secretase inhibitors showed reductions in Aβ levels in the brain.
In β-secretase inhibitors study reduced Aβ production is showed in vivo. In γ-secretase
inhibitors study, reduction of Aβ production has been showned with acute treatment in
rodents with cognitive impairment and without effect on performance in controls. Plasma
Aβ1-40 level decreased but CSF Aβ40 levels showed no significant difference. This study
suggested AD associated with Aβ might be reversible with acute pharmological treatment.
Gama-secretase is an essential protease for many substrates in addition to APP. Nonselective
inhibition of γ-secretase caused anormal differentiation of lymphocytes and inhibited Notch
signaling. Because of the side effects clinical trials were limited. Current studies based on
γ-secretase selective inhibitors and modulators are ongoing [14,15].
Similiar to γ-secretase, there are other substrates for β-secretase as peripheral nerve
myelination. Beta-secretase inhibitors caused hypomyelination of peripheral nerves at mice
[16]. Several small molecule agents of β-secretase inhibitors are under investigation.
Passive immunization, solanezumab, bapineuzumab, gantenerumab, crenezumab
and ponezumab are currently being tested. In treated patients antibodies against Aβ and
slower rates of cognitive function decline have been showed. Except neuropsychological
tests showed differences other outcomes showed no benefit and on the contrary in the
vaccinated patient’s brain volume were smaller than control group. The study stopped when
meningoencephalitis developed in 6% of patients. Further studies are needed [17].
As a NSAID tarenflurbil is a γ-secretase modulator and stil under investigation.
Tarenflurbil modulates γ-secretase to produce less toxic form of Aβ42 and reduces amyloid
plaques. In a phase II trial highest dose receiving patients showed significant benefits on
daily activities and delay of adverse events almost one year. Further testing of this agent is
ongoing.
Peroxisome proliferator-activated receptor agonists decrease Aβ42 levels through Insulin-
Degrading Enzyme (IDE). In MCI and mild AD patient’s cognitive improvement were seen
especially in patients without APOE ε4 allele. Insulin itself might improve memory in AD.
Clinic trials are still going on about peroxisome proliferator-activated receptor agonists and
intranasal insulin [18].
Receptor for Advanced Gylication End Products (RAGE) resides in blood vessel cells and
transports Aβ across the blood-brain barrier. Inhibtion of RAGE mechanism reduces Aβ
accumulation. RAGE is one of the target points of drug development in AD [19].

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Neuroprotective Approaches
Some of them supported slight delays in the progression to severe dementia. These
agents are being reconsidered [20]. Astrocyte-modulating agents are being studied. Around
Aβ plaques activated astrocytes reside and produce oxidative species. Astrocyte-modulating
agents might intervent the role of activated astrosytes in AD pathogenesis [21].
Tau-related immunotherapy aims to reduce production of intracellular neurofibrillary
tangles. Lithium reduces hyperphosphorylation of tau proteins and reduces APP but
its toxicity limits its use in older patients. Recent clinical trials reduce amyloid process
did not have convincing results on cognitive functions. Other approaches targeting NFT,
synapses loss and neuronal death came into prominence. So, active and passive tau-related
immunotherapies are in progress with promising results [22].
Studies with other compounds like nicotine acetylcholine receptor agonists, monoamine
modulators, AMPA-receptor modulators with potential benefits are in progress, but results
are not yet conclusive. NGF treatment can be applied by surgical implantation of NGF-
expressing cells or using agents that mimic endogeneous production of NGF. Xaliproden
acts by activating endogenous production of NGF and reverses hippocampal choline
acetyltransferase reduction. There are ongoing randomized, controlled, phase III trials
assessing effects of this agent [23,24] Cerebrolysin is another peptide with neurotrophic
activity and reduces Aβ accumulation. Studies demonstrated that cerebrolysin improves
daily activities and cognitive function. Clinical investigation of this agent is ongoing [25].
NGF and NGF-related agents might have neurorestorative properties and studies of these
agents are expected to continue.
Finally there are lots of the reports about disase modifying behavioral strategies and the
importance of social support in the management strategies. Also there is a growing issue
about the importance of primary prevention studies.

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