Etiology and pathogenesis Symposium

Etiology and pathogenesis of Alzheimer’s disease

MARTIN R. FARLOW

Abstract: The diagnosis, ge-
netics, risk factors, neuropa-
thology, and pathogenesis of
Alzheimer’s disease (AD) are
discussed.
AD is a degenerative brain
ible—must be ruled out by
laboratory testing and neu-
roimaging. The pathogenic
process that causes AD has
not been fully delineated;
however, it clearly leads to
ing of disease onset after age
65. Genetic factors may pro-
mote or accelerate deposition
of β-amyloid protein to form
plaques, as well as abnormal
phosphorylation of tau pro-
systems, leading to cognitive
dysfunction, psychiatric and
behavioral disturbances, and
eventual loss of ability to per-
form ADL.
The etiology and patho-

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disorder and is the leading
cause of dementia. Clinical
manifestations of AD are pri-
marily the progressive loss of
memory and language. Other
signs and symptoms of the
disease include psychiatric
and behavioral disturbances
and impairments in the per-
formance of activities of daily
living (ADL). To diagnose AD,
other causes of dementia—
some of which may be revers-
neuropathology characterized
by neuritic plaques, neuro-
fibrillary tangles, and loss of
cholinergic neurons in the
nucleus basalis of Meynert.
Genetic factors, including
mutations in the amyloid
precursor protein and the two
presenilin genes, appear im-
portant in the development
of early-onset familial AD,
whereas the apolipoprotein E
genotype influences the tim-
tein to form neurofibrillary
tangles. Several biochemical
factors, such as inflamma-
tion, oxidative stress, and
hormonal deficiency (estro-
gen), and other unmodifiable
risk factors, notably aging,
also play a role in the patho-
genic process. The loss of
neurons and synaptic con-
nections is selective and caus-
es deficiencies in cholinergic
and other neurotransmitter
genesis of AD are highly
complex; more effective ther-
apeutic approaches than
those currently available will
be needed to address these
underlying factors more spe-
cifically.
Index terms: Alzheimer’s
disease; Diagnosis; Genetics;
Geriatrics; Research
Am J Health-Syst Pharm.
1998; 55(Suppl 2):S5-10

A lzheimer’s disease (AD) is a neurodegenerative

disorder that is the most common cause of de-
mentia in the industrialized world. It affects an
estimated 4 million people in the United States alone, a
figure that is expected to triple over the next 50 years as
the elderly population grows.1 The risk of AD increases
with age, with the incidence doubling every 5.1 years
after age 40; 50% or more of the population over age 85
is afflicted.2,3
The clinical characteristics of AD are primarily cogni-
tive deficits that progressively worsen over several
years. With disease progression, patients may have
psychiatric and behavioral disturbances and always
progressively lose the ability to perform activities of
daily living (ADL). In contrast, other forms of cognitive
dysfunction, such as transient ischemic attacks and
seizures, occur over minutes to hours. Between these
two temporal extremes, other sources of cognitive dys-
function, such as tumors, chronic subdural hemato-
mas, and Creutzfeldt-Jakob disease, cause symptoms
that progress over weeks or months. Creutzfeldt-Jakob
disease is a very rare cause of dementia that results in
rapid deterioration, with death occurring six months to
one year after onset. It may be transmitted by a special
protein called a prion that reproduces itself, is infec-
tious, and may cause a version of Creutzfeldt-Jakob
disease known as mad-cow disease.4
AD may be distinguished by clinical means from
three other very slowly developing neurodegenerative
illnesses: frontotemporal dementia (FTD), dementia
with Lewy bodies, and vascular dementia (Figure 1).
FTD, which includes Pick’s disease, may account for up
to 4% of dementia cases. It causes atrophy of the frontal
lobes of the brain, with corresponding enlargement of
the frontal horns of the lateral ventricles. Clinically,
FTD is characterized by lack of initiative, apathy, poor
goal setting, diminished executive function (planning
and decision-making), and disinhibition (lack of emo-
tional or behavioral control). In the early stages, behav-
ioral abnormalities are usually more prominent than

MARTIN R. FARLOW, M.D., is Professor and Vice Chairman for
Research, Department of Neurology, School of Medicine, Indiana
University, Indianapolis.
Address reprint requests to Dr. Farlow at the Alzheimer’s Dis-
ease Center, Indiana University School of Medicine, 541 North
Clinical Drive, Suite 583, Indianapolis, IN 46202-5111 (mfarlow
@iupui.edu).
Based on the proceedings of a symposium held December 8,
1997, at the ASHP Midyear Clinical Meeting in Atlanta, Georgia,
and supported by an unrestricted educational grant from Bayer
Corporation Pharmaceutical Division.
Dr. Farlow received an honorarium for participating in the
symposium and preparing this article. He is a clinical investigator
for Bayer Corporation Pharmaceutical Division; Eisai Co., Ltd.; Eli
Lilly and Company; Janssen Pharmaceutica Inc.; Novartis Phar-
maceuticals Corporation; Parke-Davis; Sigma Tau; Somerset Phar-
maceuticals, Inc.; Takeda USA; and Wyeth-Ayerst Laboratories. He
has served as a consultant for Bayer Pharmaceutical Division, Eli
Lilly and Company, Novartis Pharmaceuticals Corporation, Quin-
tiles Transnational Corp., and Wyeth-Ayerst Laboratories. He par-
ticipates in the speaker panels for Bayer Pharmaceutical Division,
Novartis Pharmaceuticals Corporation, Pfizer Inc., and Wyeth-
Ayerst Laboratories.
Copyright © 1998, American Society of Health-System Phar-
macists, Inc. All rights reserved. 1079-2082/98/1101-00S5$06.00.

Vol 55 Nov 1 1998 Suppl 2 Am J Health-Syst Pharm S5

Symposium Etiology and pathogenesis
Figure 1. Important clues aiding in the differential diagnosis of Alzheimer’s disease (AD). Other causes of dementia can be differentiated
from AD by differing temporal profiles, signs of preceding stroke, parkinsonian signs, hallucinations, and other behavioral abnormalities.
EPS = extrapyramidal symptoms.
Alzheimer’s
Disease
▲
lts d
su n
▲
re le a
ry fi
to ro
ra l p
bo ra
la po
m
Te
ke
▲
Stro
Rapidly
evolving
dementias
▲ ▲
Vascular
dementia
memory problems. Dementia with Lewy bodies has
been recognized neuropathologically with increasing
frequency since new monoclonal antibodies were de-
veloped that better demonstrate these intracytoplasmic
neuronal inclusions. Up to 13% of all dementia cases
may be caused by widespread cortical or subcortical
involvement of diffuse Lewy bodies.5 Clinically, this
illness is characterized by early onset of delusions,
hallucinations or psychosis, extrapyramidal signs, fluc-
tuating deficits, and more rapid progression than in
AD. At autopsy, many patients demonstrate both Lewy
bodies and the neuropathologic changes of AD. Vascu-
lar dementia is caused by cortical or subcortical strokes
that cause temporally linked decreases in cognition.
Typically, in patients with multi-infarct-related demen-
tia, there are clinical focal signs (present on examina-
tion) consistent with previous stroke.
This article discusses the diagnosis, genetics, risk
factors, neuropathology, and pathogenesis of AD.
Diagnosis
Dementia is characterized by a deficit in short-term
memory and by other cognitive deficits, such as impair-
ments in orientation, language, constructional ability,
problem solving, abstract thinking, and praxis, that
gradually worsen over a period of at least six months.
AD is the most common cause of dementia (about 70%
of cases).b The diagnosis is made by documenting the
presence of dementia and then excluding other causes
based on history, physical examination, and laboratory
and neuroimaging studies. Information should be ob-
tained from a spouse, close relative, or caregiver in
order to verify the patient’s statements and the decline
in ADL, risks to patient safety, and familial history of
S6 Am J Health-Syst Pharm Vol 55 Nov 1 1998 Suppl 2
▲
Be ent
▲
m
ha al s
vio ta
hallu EPS
r a tus
nd
cinat
Visua s and
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▲
ion
l
Frontotemporal
dementia
Dementia
with Lewy
bodies
dementia or related conditions. While memory loss and
cognitive dysfunction are the core symptoms, AD com-
monly causes other symptoms that affect behavior and
daily functioning. Other medical conditions may be
present and must be excluded as principal causes of the
dementia. These conditions may worsen dementia in
AD but are not the principal cause.
The patient’s mental status, including orientation,
learning, naming, drawing, and judgment skills, should
be evaluated with a standardized instrument, such as
the Mini-Mental State Examination (MMSE).7,8 This 30-
point test can be administered in a clinic or office in
approximately five minutes. Whereas test results may
be affected by the level of education,9 adjusted norms
that take this factor into consideration are available.10
In a large cohort of adults, the median score was 29 for
those with at least nine years of education, but the score
dropped to 26 for those with five to eight years of
schooling and was only 22 for those with zero to four
years. Among patients 80 years of age or older, the
median score was 25. Therefore, a score of less than 26
in a patient with a high school education should flag
the potential presence of underlying AD.
Several conditions potentially causing dementia may
be reversible, including hypothyroidism, vitamin B12
deficiency, cerebral vasculitis, and neurosyphilis.1 These,
however, rarely present a clinical profile that is typical of
AD. Laboratory and neuroimaging studies are used to
exclude reversible causes of dementia. An appropriate
laboratory investigation should include complete blood
count, electrolytes, liver and thyroid function, erythro-
cyte sedimentation rate (ESR), serum B12 and folate, and
syphilis serology. In practice, hypothyroidism is the most
common cause of reversible dementia, and dementia in

patients with vasculitis and an elevated ESR may some-
times be reversed with treatment. In contrast, dementia
in patients who are found on evaluation to have vitamin
B12 deficiency but no other neurologic signs is seldom
truly reversible. Computerized tomography or magnetic
resonance imaging of the brain should be performed to
exclude structural problems, such as hydrocephalus,
strokes, tumors, and subdural hematomas. These imag-
ing studies may show selective hippocampal atrophy in
AD, but changes may not be present early in the illness.
If the course or history of dementia is atypical,
additional tests may be useful for establishing a diagno-
sis. These include lumbar puncture, single photon
emission computerized tomography (SPECT), and
positron emission tomography (PET). Lumbar puncture
is no longer routinely performed unless a rapid course
of illness, fever, or other neurologic signs suggests
infection or vasculitis. There are commercially available
cerebrospinal fluid tests for AD that include tests for β-
amyloid protein (decreased levels), tau protein (in-
creased levels), and neural thread protein (decreased
levels). However, the role of these markers in the diag-
nosis of AD remains controversial.11 PET and SPECT
scans typically show hypometabolism in the posterior
parietal lobes. In particular, PET may be useful in help-
ing to differentiate AD from other dementias, but its use
is limited by high cost and lack of consistent reimburse-
ment by third-party payers. It is therefore reserved for
research purposes and special clinical situations.
Finally, chromosomal mutations known to cause
hereditary AD may be detected in some members of rare
families, and determining the apolipoprotein E geno-
type of persons with dementia may improve accuracy
of diagnosis in a somewhat greater number of patients.
Genetics
Mutations in the amyloid precursor protein (APP)
gene on chromosome 21 were the first genetic muta-
tions to be directly linked to early-onset familial AD.12
APP is a cell surface membrane-spanning protein of 695
to 770 amino acids that is cleaved proteolytically to
form β-amyloid proteins, a family of peptides consist-
ing of 39 to 43 amino acids each. Extracellular plaques
composed largely of β-amyloid are a hallmark of AD.
Some of the disease-associated mutations may subtly
alter the position at which cleavage of APP occurs,
resulting in more β-amyloid peptides containing 42 or
43 amino acids, which are less soluble and more prone
to aggregation.13 Other mutations shift APP processing
to the β-secretase rather than α-secretase pathway, in-
creasing levels of intracellular, potentially amy-
loidogenic, β-proteins. Thus, genetic mutations may
facilitate amyloid deposition and cause AD by different
mechanisms.
A second gene, known as presenilin-1, is located on
chromosome 14. More than 30 families from a variety
of ethnic backgrounds with early-onset AD have been
Etiology and pathogenesis Symposium
found to have various missense mutations in the pre-
senilin-1 gene that are linked to the disease.12 This gene
encodes a transmembrane protein having 467 amino
acids; its function remains unknown. A gene with
sequence homology to presenilin-1 that also causes
early-onset AD in families is found on chromosome 1
and is known as presenilin-2. It encodes a very similar
transmembrane protein, which has 448 amino acids
and 67% identity with the presenilin-1 protein. Because
only two missense mutations in the presenilin-2 gene
have been found to be associated with early-onset AD,
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this mutation likely accounts for only a small propor-
tion of cases of familial AD. The identified missense
mutations in the presenilin-1 and presenilin-2 genes
occur in regions that are conserved between the two
genes, suggesting that both proteins subserve a similar
function.13 However, cell-line studies suggest that dis-
ease-associated mutations in both presenilin genes
seem to increase the production or level of APP. Prese-
nilin proteins are expressed in a wide range of organs
other than the brain, including the heart, placenta,
lungs, and liver; the function of these proteins in these
other organs is also unknown.
Mutations in the APP gene and both presenilin genes
are found in less than 1% of all patients with AD. In
comparison, a major genetic factor that seems to influ-
ence time of onset in late-onset AD is the apolipoprotein
E genotype. Apolipoprotein E is a lipid-transport protein
in serum and the major lipid transporter for the central
nervous system.13,14 The gene coding for apolipoprotein
E has three alleles, ε2, ε3, and ε4. Allele frequencies in
Western European populations are approximately 15%
for ε4, 75% for ε3, and 10% for ε2, with the ε4 allele
being associated with dyslipidemia and coronary artery
disease. As many as 65% of AD patients carry at least
one copy of ε4.14 People who inherit two copies of ε4
have a 50% chance of developing AD in their middle to
late 60s (Figure 2).14,15 However, many people homozy-
gous for ε4 live into their 80s or 90s with no signs of AD.
Figure 2. Association of risk for Alzheimer’s disease (AD) with
apolipoprotein E genotype. The percentage of patients develop-
ing AD by a given age is shown for patients with two copies (ε4/
ε4), one copy (ε4), or no copies (ε2/ε3) of the ε4 allele. Reprinted
from reference 13, with permission.
1.0
0.8
% Patients
0.6 ε2/εε3
0.4 ε4
0.2 ε4/εε4
0.0
60 65 70 75 80 85 90
Age at Onset of AD (yr)
Vol 55 Nov 1 1998 Suppl 2 Am J Health-Syst Pharm S7
Symposium Etiology and pathogenesis
People with one copy of ε4 have a 50% chance of
developing AD in their mid-70s, whereas people who
do not have ε4 may not develop AD before their mid-
80s, if at all. In contrast, the ε2 allele may actually
reduce the risk for or delay the onset of AD.13,14
Although the apolipoprotein E genotype is an im-
portant genetic risk factor, it cannot predict which
patient will develop AD, nor can it be used as an
independent test to confirm the diagnosis of AD. A
retrospective analysis of AD patients who participated
in a 30-week, double-blind trial of tacrine suggested
that this drug was significantly more effective among
patients without the ε4 allele than among those with it,
especially after the patient’s disease stage was added as
a covariant.14 An analysis of data pooled from four large
metrifonate (trichlorfon) trials involving a relatively
low dose (30–60 mg) was performed to investigate
whether an interaction exists between cholinesterase
inhibitor therapy and the apolipoprotein E genotype
and whether the genotype independently affects the
rate of disease progression.16 The analysis provided no
evidence to suggest that the apolipoprotein E genotype
significantly influenced the response to metrifonate
treatment—a result not consistent with a previous post
hoc analysis of tacrine’s efficacy.17 Potential factors that
might cause divergence in this pharmacogenetic inter-
action include differences in pharmacokinetic and
pharmacodynamic profiles of metrifonate and tacrine
and differences in the degree of cholinesterase inhibi-
tion achieved by the two drugs in these studies.16
Neuropathology and pathogenesis
AD is characterized by a progressive pathogenic
process that kills neurons and destroys synaptic con-
nections.18 The initiating event in this process remains
unclear. As a consequence of neuronal loss, there is
generalized ventricular and sulcal enlargement and
cortical atrophy.
The disease is traditionally characterized by the pres-
ence of neuritic plaques and neurofibrillary tangles
throughout the cortex and loss of cholinergic neurons
from the nucleus basalis of Meynert. However, the
neuropathology is actually even more complex. There
is a general loss of neurons, particularly medium-sized
and large pyramidal cells, and their synaptic connec-
tions. The hippocampus, entorhinal cortex, and neo-
cortex are the regions that are most severely affected,
although significant neuronal loss occurs in other re-
gions of the brain, including the locus ceruleus, dorsal
raphe, and other brain stem nuclei. These neuronal
losses result in deficits in other neurotransmitter sys-
tems, including the noradrenergic, dopaminergic, and
serotonergic systems—abnormalities that contribute to
the behavioral and psychiatric symptoms commonly
present in patients with AD.
The core of neuritic plaques is composed of β-amy-
loid that has aggregated into densely packed, insoluble,
S8 Am J Health-Syst Pharm Vol 55 Nov 1 1998 Suppl 2
β-pleated sheets.18 The β-amyloid core is surrounded by
dystrophic neurites and abnormal synapses, with acti-
vated microglia and fibrous astrocytes located on the
periphery. The association of mutations in the APP
gene with early-onset AD supports the concept that β-
amyloid plays a significant causal pathogenic role in
AD. Beta-amyloid appears to be directly neurotoxic,
and it may induce microglial cells to release a variety of
inflammatory mediators, including interleukin-1 (IL-
1), complement proteins, reactive oxygen species, and
excitotoxins, which in turn may contribute to neu-
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ronal damage and loss. Because the physiological func-
tion of APP is undefined, its role and that of β-amyloid
proteins as primary contributors to the disease process
are still to be defined. It is possible that they are
secondary contributors to a disease process that begins
entirely differently.19
Neurofibrillary tangles are also a neuropathologic
hallmark of AD. They consist of paired helical filaments
that are composed predominantly of abnormally phos-
phorylated tau protein combined with other, lesser
components.18,19 Under normal conditions, tau binds
to and stabilizes microtubules; it is therefore an impor-
tant element of the neuronal cytoskeleton.20 In AD,
abnormally phosphorylated tau is no longer able to
bind to microtubules, which may lead to microtubular
destabilization and retrograde axonal degeneration.21
Neurofibrillary tangles are commonly found inside
medium-sized and large neurons of the entorhinal area,
hippocampus, and neocortex. The presence and extent
of tangle deposition in the brain are more closely
correlated with cognitive impairment in AD than is the
density of neuritic plaques.18 Nevertheless, it is more
likely that β-amyloid deposition rather than abnormal
phosphorylation of tau is the primary pathogenic factor,
because all three genes associated with hereditary AD
alter metabolism to increase APP or β-amyloid protein.
In brains from AD patients, apolipoprotein E is
found in association with both neuritic plaques and
neurofibrillary tangles; however, the predominant
mechanism by which this protein contributes to the
disease remains a mystery. Any theory concerning the
pathogenesis of AD must explain why the ε4 allele of
the gene coding for apolipoprotein E increases the risk
of developing the disease at an earlier age. Several in
vitro studies may offer some insight. The ε3 allele binds
to the region on tau that is believed to be involved in
the formation of the paired helical filaments. By com-
parison, ε4 has a lower affinity for tau than the other
alleles; therefore, it may be unable to prevent the
abnormal phosphorylation of tau and the subsequent
development of neurofibrillary tangles.22 The ε4 allele
appears more likely than the other alleles to bind to β-
amyloid, especially after oxidation.23 Most convincing
are experiments in which a transgenic animal with a
mutation in the APP gene and amyloid deposits is
crossed with another animal with knockout of the

apolipoprotein E gene (i.e., with a damaged gene that
no longer produces a functional protein.24 Offspring
with both the APP gene mutation and apolipoprotein E
gene knockout did not develop plaques, suggesting that
the most significant action of apolipoprotein E may be
in binding to β-amyloid and facilitating the formation
of plaques. This interaction may be important in β-
amyloid aggregation; however, it still does not prove
this mechanism is predominant in causing AD for most
of the human population, in which mutations in the
APP gene are not found.
Other factors may play a role in the pathogenesis of
AD. Inflammation appears to contribute, since cyto-
kines and other proteins associated with inflammation,
such as IL-1, several acute-phase proteins (IL-6, α1-
antichymotrypsin, α2-macroglobulin), and comple-
ment components C3 and C4 are found in brains from
AD patients but not in brains from age-matched con-
trols.25,26 It remains to be determined whether these
mediators of inflammation contribute to the pathogen-
esis of AD or are markers of the neurodegenerative
process. IL-1 may play a role in converting diffuse plaques
into neuritic plaques; in vitro studies suggest that IL-1
can stimulate secretion of APP and augment the neu-
ronal toxicity of β-amyloid.27 Complement activation
leading to generation of membrane attack complex
could, in theory, contribute to the destruction of neu-
ronal membranes. Activated microglial cells, which are
associated with neuritic plaques but not diffuse ones,
may be the source of these mediators; they are antigen-
presenting cells that produce cytokines, acute-phase pro-
teins, and complement.27 Several large epidemiologic
studies demonstrate that previous corticosteroid use or
daily use of nonsteroidal anti-inflammatory drugs
(NSAIDs) reduces the risk of AD.28,29
Several other biochemical factors may influence the
pathogenesis of AD. These include free radicals, which
may hasten neuronal degeneration, and deficits in
estrogens, which may play a role in neuroprotection by
enhancing the actions of nerve growth factor, particu-
larly in protecting cholinergic neurons. These hypoth-
eses have spurred clinical studies evaluating the efficacy
of the antioxidant vitamin E and estrogen replacement
therapy in AD.
Factors contributing to the pathogenesis or
modified progression of AD
AD involves multiple factors that contribute to the
observed neuropathology (Figure 3). Genetic factors,
including APP, the presenilin gene products, and the
apolipoprotein E genotype, influence the risk of AD. A
search for effective drugs to block these factors is just
beginning. A number of biochemical factors, such as
inflammation, oxidative stress, nerve growth factor
deficits, and estrogen deficiencies, likely contribute to
the progression of AD. Several trials of investigational
drugs that may delay disease progression by modifying
Etiology and pathogenesis Symposium
Figure 3. Risk factors for Alzheimer’s disease and their relation-
ship to its pathogenesis. APP = amyloid precursor protein.
Genetic Factors
• APP mutations
• Presenilin 1 and 2
• Apolipoprotein ε4
▲
Neuropathology
Biochemical Factors • β-Amyloid deposits
• Inflammation • Neurofibrillary tangles
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▲
• Free radical • Neuronal loss
• Nerve growth factor deficit • Synaptic loss
• Estrogen deficit ▲ ▲
Unmodifiable Risk Factors Neuropathologic Outflow
• Age • Cholinergic deficit
• Head size • Noradrenergic deficit
• Education level • Serotonergic deficit
• Sex
these factors are in progress. Other risk factors include
advanced age, smaller head size, and possibly a lower
level of education. Higher levels of education may
increase functional reserve capacity; more-educated
people may be better able to maintain ADL for longer
periods while cognitive performance progressively de-
clines.30 Alternatively, people with less education, who
for the most part are poorer, may be at higher risk
because they may have fewer interneuronal interac-
tions and less reserve. These latter risk factors are, in
general, difficult or impossible to modify.
The neuropathologic changes—β-amyloid deposits
in neuritic plaques, neurofibrillary tangles, and loss of
neurons and synapses—lead to selective deficits in neu-
rotransmitter systems, with cholinergic function being
the most severely affected. Cholinergic loss in the nu-
cleus basalis of Meynert, the basal forebrain site where
the magnocellular cholinergic neurons that project to
the neocortex are located, is believed to be primarily
responsible for deficits in memory and learning in
AD.31 The loss of cholinergic neurons in the nucleus
basalis and the loss of cholinergic markers in the cortex
correlate best with mental test scores in AD patients. As
a result, therapeutic efforts to improve cognitive perfor-
mance in AD patients have focused on augmenting
cholinergic function, either with cholinesterase inhibi-
tors or selective muscarinic agonists. Recently, cholinest-
erase inhibitors had positive effects in controlling psychi-
atric symptoms or abnormal behaviors.32 In addition to
cholinergic deficits, reductions in other neurotransmit-
ter systems, including the serotonergic and adrenergic
systems, likely contribute to behavioral and psychiatric
symptoms, such as mood, behavior, sleep disturbances,
and depression. These symptoms are treated with antip-
sychotic and antidepressant drugs that act on these
neurotransmitter systems.
Vol 55 Nov 1 1998 Suppl 2 Am J Health-Syst Pharm S9
Symposium Etiology and pathogenesis
Conclusion
Current therapeutic approaches to treating Alz-
heimer’s disease have targeted neurotransmitter defi-
cits; however, these approaches do not address the
underlying factors involved in the pathogenesis of AD.
It is hoped that better recognition of genetic factors and
the underlying pathogenic processes that are important
in AD will lead to more effective therapeutic approach-
es than are currently available.
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