OUTLINE

 Introduction

 Epidemiology

 Etiology

 Pathophysiology

 Clinical presentation

 Diagnosis

 Treatment
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 [Auguste Deter, Alois Alzheimer's patient in
November 1901, first described patient with
Alzheimer's Disease.]

[1864 - Dr. Alois Alzheimer, psychiatrist,

pathologist, born in Marktbreit, Bavaria]
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 INTRODUCTION

• Alzheimer disease (AD) is characterized by progressive

cognitive decline including memory loss, disorientation,
and impaired judgment and learning.
• Patients eventually lose cognitive, analytical, and
physical functioning, and the disease is ultimately fatal.

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 EPIDEMIOLOGY AND ETIOLOGY

 Alzheimer’s is predicted to affect 1 in 85 people globally

by 2050.
 AD is the most common type of dementia, affecting an
estimated 5.2 million Americans in 2014.
 Most cases occur age >65 years (late onset)
 5% of cases occur age <65 years (early onset)
 The mean survival time of persons with AD is reported to
be approximately 6 years from the onset of symptoms.
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 Etiology
 The exact etiology of AD is unknown.
 Genetic, Environmental, and Lifestyle factors.
Genetic factors
 Alterations to chromosomes 1 (protein, presenilin 2), chromosome 14
(protein, presenilin 1) and chromosome 21 (amyloid precursor protein
(APP)) lead to an increase in β-A4 peptide fragments of APP which
forms neuritic plaques are associated with early onset AD, whereas,
 The presence of apolipoprotein E (apo E) E4 alleles on chromosome 19
increases risk of developing late-onset AD.
 There are three variants of apo E (apo E2, apo E3, and apo E4); however,
Carriers of two or more of the apo E4 allele have an earlier onset of AD
(approximately 6 Years earlier) compared with non-carriers.
 The mechanism is unknown.

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 Etiology…

 Mutations in the tau gene on chromosome 17 is associated with an

abnormality in tau protein and development of neurofibrillary
tangles.

Environmental factors are:

 Age
 risk factors for vascular disease
 Decreased reserve capacity of the brain
 Head injury.

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 Pathophysiology
 Neuropathologic hallmarks of AD include
neurofibrillary tangles (NFTs) and neuritic
plaques.
 Degeneration of neurons, synapses, cortical atrophy,
 a shortage of acetylcholine occurs.

Several hypothesis have been proposed to explain

these changes in the brain.

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 Pathophysiology…
Amyloid cascade hypothesis
 B- amyloid plaques are clumps of insoluble
peptides result from abnormal cleavage of
amyloid precursor protein (APP)

 APP normally cleaved by 3 enzymes

In AD, a variant form of the γ-secretase cleaves
APP
 a 42 amino acid peptide called AB which is not soluble and
aggregate in to identifable clumps termed B- amyloid plaques
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Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward.
It is though to be important for neuronal growth, survival, and repair.

From: www.niapublications.org/pubs/unraveling/01.htm 11
Enzymes cut the APP into fragments, the most important of which for AD is called -amyloid
(beta-amyloid) or A.
From: www.niapublications.org/pubs/unraveling/01.htm 12
 Beta-amyloid is “sticky” so the fragments cling together along with other material outside
of the cell, forming the plaques seen in the AD brain.
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From: www.niapublications.org/pubs/unraveling/01.htm
 Pathophysiology…
Neurofibrillary tangles
 A protein called Tau stabilizes the microtubules when
phosphorylated (microtubule-associated protein)
Tau undergoes chemical changes, (hyperphosphorylated) then
begins to pair with other threads, creating neurofibrillary
Tangles and disintegrating the neuron's transport system.
• Tangles are insoluble even after the cell dies. and they cannot
be removed once established, thus prevention is key.
 The neurons that provide most of the cholinergic innervations
to the cortex are most prominently affected.

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 Pathophysiology…
Acetylcholine
 Ach; transmit messages between certain nerve cells in the brain.
 In AD, the plaques and tangles damage multiple neuronal pathways,
leading to a shortage of Ach, resulting in learning and memory
impairment.
Cholesterol
 The cholesterol increases β-amyloid protein synthesis which can lead to
plaque formation.
Estrogen
 protect memory loss associated with normal aging.
 may block β-amyloid protein production and even trigger nerve growth.
 Is also an antioxidant and helps prevent oxidative cell damage.
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 Pathophysiology…
Glutamate
 Is excitatory neurotransmitter and involved in memory, learning, and
neuronal plasticity.
 It acts by providing information from one brain area to another. In AD,
One type of glutamate receptor, NMDA, is less prevalent than normal.
 Over activation of unregulated glutamate signaling.
 This results in a rise in calcium ions that induces secondary cascades
which lead to neuronal death and an increased production of APP.
 The increased production of APP is associated with higher rates of
plaque development and hyperphosphorylation of tau protein.

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 Pathophysiology…

The Chronic inflammation hypothesis

• B-amyloid deposits, NFTs, and damaged
neurons may stimulate inflammation

• In AD, microglia activated to release

potentially cytotoxic molecule. This process
proceed uninhibited, causing more harm than
protection

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 Pathophysiology…

Other neurotransmitter deficiencies

• Serotonin – affective illness

• Norepinephrine - behavioral and psychological

symptoms of dementia, in addition to memory
loss

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 CLINICAL PRESENTATION

 The patient may have vague memory complaints initially, or other

may report that the patient is “forgetful.”

 Cognitive decline is gradual over the course of illness.

 Behavioral disturbances may be present in moderate stages.

 Loss of daily function is common in advanced stages.

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 Symptoms
Cognitive
 Memory loss (poor recall and losing items)
 Aphasia
 Apraxia
 Agnosia
 Disorientation (impaired perception of time and unable to recognize
familiar people)
 Impaired executive function

Noncognitive
 Depression, psychotic symptoms (hallucinations and delusions)
 Behavioral disturbances (physical and verbal aggression, motor hyperactivity,
uncooperativeness, wandering, repetitive mannerisms and activities, and
combativeness)
 Functional
Inability to care for self (dressing, bathing, toileting, and eating)
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 Stages of Alzheimer’s Disease

Mild (early stage)

 Difficulty remembering recent events.
 Declines ability to manage finances, prepare food, and other household activities
 May get lost while driving, give up hobbies.
 May deny memory problems.
Moderate (mid stage )
 Requires assistance with activities of daily living.
 Frequently disoriented with regard to time (date, year, season).
 May forget some details of past and names of family and friends.
 Agitation and delusions are common.
Severe (late stage)
 Patient loses ability to speak, walk, and feed self.
 Incontinent of urine and feces.
 Requires care 24 hours a day, 7 days a week. 21
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 Diagnosis
Diagnostic Criteria for Alzheimer’s Disease Based on DSM-IV-TR
A. The development of multiple cognitive deficits manifested by both
(1) Memory impairment
(2) one or more of the following cognitive disturbances:
(a) aphasia
(b) apraxia
(c) agnosia
(d) disturbance in executive functioning

B. The cognitive deficits in criteria A1 and A2 each cause significant

impairment in social or Occupational functioning and represent a
significant decline from a previous level of functioning.
C. The course is characterized by gradual onset &continuing cognitive decline.

D. The cognitive deficits in criteria A1 and A2 are not due to any of the
following:
(1) other CNS conditions that cause progressive deficits in memory and cognition
(2) systemic conditions that are known to cause dementia
(3) substance-induced conditions
E. The deficits do not occur exclusively during the course of delirium. 23
 Diagnosis…
 The Mini-Mental Status Examination (MMSE) is widely used to
evaluate the cognitive impairments needed for diagnosis.
 Functional evaluation, and a caregiver interview.
 physical examination as well as laboratory tests (CBC, serum
electrolytes, LFT, TFT , and a vitamin B12 level) to help
determine if it is dementia, as well as rule out any other causes.

In some cases,
 CT or MRI (often visible atrophy or shrinking of the brain)
 Neuropsychological testing is also optional, can help to establish a
neuroanatomical localization for the patient’s cognitive deficits.
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 Treatment
Desired outcome
 None of the agents are curative or can not directly reverse the
disease process.

 The primary goal is to maintain patient functioning as long as

possible.

 Secondary goals are treating psychiatric and behavioral

symptoms that may occur during the course of the disease.

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 General t/t approach

The current gold standard of treatment includes:

 Pharmacologic management with a cholinesterase (ChE)

inhibitor (tacrine, rivastigmine, galantamine, and donepezil)
and/or an NMDA antagonist.

 The use of tacrine is limited due to its propensity for

hepatotoxicity and difficult titration schedule.

 Psychiatric and behavioral symptoms should be treated as they

occur.

Education, communication, and planning with the

family/caregiver is essential elements in the treatment of AD.
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 Non pharmacologic Treatment
Nonpharmacologic therapy
 The patient and family should be counseled
 Creating a calm environment and removing stressors and
triggers.
Basic principles in the treatment of patients with AD
include:
 Using a gentle, calm approach to the patient
 Giving reassurance when needed
 Empathizing with the patient’s concerns
 Maintaining daily routines
 Providing a safe environment
 Providing daytime activities
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 Pharmacologic therapy

• Managing blood pressure, cholesterol, and

blood sugar may reduce the risk of developing
AD and may prevent the worsening of
dementia in patients with AD

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 Pharmacologic therapy…
Cholinesterase inhibitors
• For Mild/Moderate AD: while donepezil is also
indicated in severe AD
 increase the levels of acetylcholine in the brain.
 Treatment should begin as early as possible.

Patients should be switched to another ChE inhibitor

from their initial one. if they show;
 an initial lack of efficacy;
 initially respond to treatment, but lose clinical benefit;
or
 experience safety/tolerability issues.
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 Pharmacologic therapy…

Therapy should be discontinued in patients who

experience;
 poor tolerance or compliance,
 lack of clinical improvement after 3 to 6 months
 continue to deteriorate at the pretreatment rate, or
who demonstrate dramatic clinical deterioration
following initiation of treatment.

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 Pharmacologic
PharmacologicTreat. Cont…
therapy…
1. Donepezil
 reversibly and non-competitively inhibits centrally active
acetylcholinesterase.
 result in fewer peripheral side effects as compared to the other ChE
inhibitors.
 dose of 5 mg/day. increased to 10 mg/day if needed after 4 to 6
weeks.
 Abrupt discontinuation can cause worsening of cognition and
behavior
 have a small number of drug interactions.
 S/E: nausea, vomiting, and diarrhea.

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 Pharmacologic therapy…
2. Rivastigmine
 has central activity for both the acetylcholinesterase and
butyrylcholinesterase enzymes
 initial dose of 1.5 mg twice daily; if this dose is tolerated
Increased to 3 mg, 4.5 mg and 6 mg twice daily.
 should be attempted only after at least 2 weeks at the
previous dose.
 Tolerability and absorption are improved when the dose is
given with food.
S/E: nausea, vomiting, and diarrhea common, but are usually
well tolerated.
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 Pharmacologic therapy…
3. Galantamine
 elevates acetylcholine in the cerebral cortex.
 also stimulates nicotinic receptors to release more acetylcholine in
the brain.
 It may increaseglutamate and sertonin level
 initial dose is 8 mg daily (or 4 mg twice daily) for 4 weeks. If
tolerated,
 increased to 16 mg daily (or 8 mg twice daily) for at least 4 weeks.
 Again, if this dose is tolerated, increased if needed to 24 mg daily
(or 12 Mg twice daily).

S/E nausea, vomiting, and diarrhea.

CYP3A4 and 2D6 are the major enzymes involved in the metabolism.
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 PharmacologicTreat.
Pharmacologic therapy…
Cont…
NMDA receptor antagonist:
Memantine
 A non-competitive antagonist of the NMDA type of
glutamate receptors,
 control the amount of calcium that enters the nerve cell.
 A suggested titration is: 5 mg/day for at least 1 week;
 5 mg twice daily for at least 1 week;
 15 mg/day (5 mg in the morning and 10 mg in the evening)
for at least 1 week; then 10 mg twice daily.
 Monotherapy or combination with ChE inhibitors.
S/E constipation, confusion, dizziness, headache, coughing,
and hypertension. 37
 Pharmacologic therapy…

Non-conventional Pharmacologic Treatment

• Vitamin E has often been recommended for use as an
adjuncive t/t?

• estrogen - trials do not support the use

• NSAID are not recommended for t/t or prevention of AD.

• Pravastatin and lovastatin, but not simvastatin, were

associated with a lower prevalence of AD. Further study is
needed

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 Treatment for Behavioral Symptoms
Nonpharmacologic:
• Music
• Videotapes of family members
• Audio tapes of the voices of caregivers
•Walking and light exercise
• Sensory stimulation and relaxation
Pharmacologic:
 atypical antipsychotics are the preferred agents for the
treatment of psychosis and the disruptive behaviors (agitation
and aggression) of Alzheimer’s disease.
 risperidone and olanzapine (not for elder AD pts)
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 Treatment for Behavioral Cont…
• Citalopram and sertraline, Treatment of depression with
AD.
• Indications for the use of antidepressants include
depression characterized by poor appetite, hopelessness,
anhedonia, withdrawal, duicidal thoughts, and agitation.
• Benzodiazepines for anxiety, agitation, and aggression.
• potential for hip fractures in the elderly.

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 OUTCOME EVALUATION
• subjective information from the patient and the caregiver,

• MMSE can be a helpful tool for monitoring changes in the severity

of illness.

• There are no physical examination or laboratory parameters that are

used to evaluate the success of therapy.

• Assess improvement in quality-of-life measures such as ability to

function independently and for slowing of memory deterioration.

• Evaluate the patient for the presence of adverse drug reactions, drug
allergies, and drug interactions at appropriate intervals.

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 References
• Marie A. et al , pharmacotherapy , principle
and practice 4th edi. 2016.

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