1
Florida Heart CPR*
Alzheimer’s Disease
1 hour
Objectives: Upon Completion of this activity, the participant will be able to:
1. Understand the genetic factors associated with Alzheimer's Disease, supported
by statistical data.
2. Know the symptoms of Alzheimer's Disease and how to diagnose the disease.
3. Speak knowledgeably about methods of treatment for Alzheimer's Disease
Background: Alzheimer disease (AD) is the most common cause of dementia, which is
an acquired cognitive and behavioral impairment of sufficient severity to markedly
interfere with social and occupational functioning.
AD affects approximately 5 million people in the United States and more than 30 million
people worldwide. A larger number of individuals have decreased levels of cognitive
impairment (eg, minimal cognitive impairment), which frequently evolves into a fullblown dementia, thereby increasing the number of affected persons. The prevalence of
AD is expected to substantially increase in this century because it preferentially affects
the elderly, who constitute the fastest growing age group in many, especially
industrialized, countries. Statistical projections indicate that the number of persons
affected by the disorder in the United States will nearly triple by the year 2050.
AD is also a major public health problem from the economic perspective. In the United
States, the cost of caring for patients with AD was more than $110 billion per year in the
early 1990s, and the average yearly cost per patient is about $45,000. Because
methods for assessing the economic effects of neurodegenerative disorders are still in
their infancy, these figures must be interpreted as underestimates.
Many excellent treatises on AD have reviewed important aspects of the disorder in
considerable detail. This article is intended to be a comprehensive but not necessarily
exhaustive review of AD.
Pathophysiology: The anatomic pathology of AD includes neurofibrillary tangles
(NFTs); senile plaques (SPs) at the microscopic level; and cerebrocortical atrophy,
which predominantly involves the association regions and particularly the medial aspect
of the temporal lobe. In his original report on the disorder, Alois Alzheimer described the
co-occurrence of NFTs and SPs, which is now universally accepted as a hallmark of the
disease.
Although NFTs and SPs are characteristic of AD, they are not pathognomonic. In fact
many other neurodegenerative conditions distinct from AD are characterized by NFTs
(eg, progressive supranuclear palsy, dementia pugilistica) or SPs (eg, normal aging).
Therefore, the mere presence of these lesions is not sufficient to diagnose AD. These
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2
lesions must be present in sufficient numbers and in a characteristic topographic
distribution to fulfill the current histopathologic criteria for AD.
In addition to NFTs and SPs, many other lesions of AD have been recognized since
Alzheimer's original papers were published. These include (1) the granulovacuolar
degeneration of Shimkowicz; (2) the neuropil threads of Braak et al; and (3) neuronal
loss and synaptic degeneration, which are thought to ultimately mediate the cognitive
and behavioral manifestations of the disorder.
Some authorities believed that NFTs, when present in low densities and essentially
confined to the hippocampus, were part of normal aging. However, the histologic stages
for AD that Braak et al formulated includes an early stage in which a low density of
NFTs is present in the entorhinal and perirhinal (ie, transentorhinal) cortices. Therefore,
even small numbers of NFTs in these areas of the medial temporal lobe should be
considered abnormal. The issue of whether these early changes should be considered
part of minimal cognitive impairment (Kuljis, 1997) or the early stages of AD instead
remains to be settled experimentally.
In contrast, the presence of even low numbers of NFTs in the cerebral neocortex is
considered abnormal and indicates AD if associated with SPs in that location, with a
specific topographic pattern. Granulovacuolar degeneration occurs almost exclusively in
the hippocampus and has received less attention than neuropil threads, which are an
array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less
independently of plaques and tangles. This lesion suggests neuropil alterations beyond
those merely due to NFTs and SPs and indicates an even more widespread insult to the
cortical circuitry than that visualized by studying only plaques and tangles.
Despite the wide distribution of these lesions in the cerebral cortex, the increasing
consensus is that most patients with AD have a relatively consistent topographic
pattern. NFTs are initially and most densely distributed in the medial aspect and in the
pole of the temporal lobe; they affect the entorhinal cortex and the hippocampus most
severely. As AD progresses, NFTs accumulate in most other cortical regions, beginning
in high-order association regions and less frequently in the primary motor and sensory
regions. SPs also accumulate primarily in association cortices and in the hippocampus.
Plaques and tangles have relatively discrete and stereotypical patterns of laminar
distribution in the cerebral cortex, which indicate predominant involvement of
corticocortical connections, as many investigators have observed.
According to this formulation, the pathophysiologic mechanism underlying the clinical
manifestations of AD is corticocortical disconnection due to the loss of medium-sized
pyramidal neurons effecting such connections. However, multiple lines of evidence
suggest that several classes of local circuit neurons are selectively lost throughout the
cerebral cortex as well; these data demonstrate that the corticocortical disconnection is
not the only alteration in cortical circuitry that mediates the symptoms of AD.
Frequency:
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3

In the US: The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of
individuals older than 65 years have AD, and the prevalence increases to at least
40% in individuals older than 80 years.

Internationally: Prevalences similar to those in the United States have been
reported in industrialized nations. Countries experiencing rapid increases in the
elderly segments of their population have rates approaching those in the United
States.
Mortality/Morbidity:

Second to only certain cancers and cardiovascular disease, AD is frequently
considered a leading cause of death in the United States.

The primary cause of death is intercurrent illness, such as pneumonia, in a
patient who has experienced the debilitating effects of AD for many years.
Race: Some claim that AD affects certain ethnic and racial groups more severely than
others, but more study is needed before reliable statements about racial predilections
can be made.
Sex: AD affects both men and women. Many studies indicate that the risk of AD is
significantly higher in women than in men. Some authorities have postulated that this
difference is due to the loss of the neurotrophic effect of estrogen in postmenopausal
women. Other factors may also influence this relative difference.
Age: The prevalence of AD increases with age.

AD is most prevalent in individuals older than 60 years. Some forms of familial
early-onset AD can appear as early as the third decade, but this represents a
subgroup of the less than 10% of all familial cases of AD.

More than 90% of cases of AD are sporadic and occur in individuals older than
60 years.

Of interest, results of some studies of nonagenarians and centenarians suggest
that the risk decreases in individuals older than 80 or 90 years. If so, age is not
an unqualified risk factor for the disease, but further study of this matter is
needed.
CLINICAL
History: Patients with AD most commonly present with insidiously progressive memory
loss, to which other spheres of cognitive impairment are added over several years. After
memory loss occurs, patients may also have language disorders (eg, anomia,
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4
progressive aphasia) and impairment in their visuo-spatial skills and executive
functions.
For this, the most common pattern of AD, the National Institutes of Health-Alzheimer's
Disease and Related Disorders Association (NIH-ADRDA), the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV), and the Consortium
to Establish a Registry in Alzheimer's Disease (CERAD) have formulated several clinical
guidelines for its diagnosis. The NIH-ADRDA criteria for the diagnosis of AD require the
finding of a slowly progressive memory loss of insidious onset in a fully conscious
patient. AD cannot be diagnosed in patients with clouded consciousness or delirium.
Toxic metabolic conditions and brain neoplasms must also be excluded as potential
causes of the patient's dementia.
The main focus of these diagnostic guidelines consists of verifying the initial finding of
mild, slowly progressive memory loss, that additional spheres of cognition are alter
compromised, and that other possible causes for dementia (eg, cerebrovascular
disease, cobalamin deficiency, syphilis, thyroid disease) are ruled out with a
combination of clinical examination and ancillary radiologic and laboratory tests. These
guidelines are widely believed to be 90-95% accurate (as histopathologically verified)
when followed carefully, and they are important not only for routine management but
also for selecting and enrolling patients in therapeutic trials.
Substantially less common but autopsy-proven presentations include right parietal lobe
syndrome; progressive aphasia; spastic paraparesis; and impaired visuospatial skills,
which is subsumed under the visual variant of AD. These latter, unusual presentations
often create a diagnostic challenge because the guidelines for the clinical diagnosis of
AD do not cover them. Therefore, the diagnosis is based on histopathologic or autopsy
confirmation or by ruling out previous diagnoses (eg, primary progressive aphasia,
cerebrovascular conditions, prion disorders) that had been made on purely clinical
grounds.
Physical: The earliest evidence of AD is the onset of chronic, insidious memory loss
that is slowly progressive over several years. This loss can be associated with slowly
progressive behavioral changes. Although other neurologic systems (eg,
extrapyramidal, cerebellar systems) can also be affected, the most prominent finding as
the disease progresses to its moderate and severe stages is progressive memory
impairment.
Other common neurologic presentations include changes in language ability (eg,
anomia, progressive aphasia), impaired visuospatial skills, and impaired executive
function.
Less common presentations are right parietal lobe syndrome and spastic paraparesis.
Examination in the clinic or at the patient's bedside should include a discussion with the
patient. Any cognitive impairment or language dysfunction should ideally be verified and
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Alzheimer’s Disease
5
discussed with the patient's spouse and/or caregivers. Memory dysfunction and
problems with activities of daily living (eg, cooking, cleaning, money management,
getting lost, confusion, self-care) should also be addressed.
A screening language examination and Mini-Mental Status Testing may be warranted
(see Table).
Mini-Mental Status Examination
Task and Questions
Maximum Score
Orientation
1. Ask the patient: What year, season, date, day, and month is it?
2. Ask the patient: What state, country, town, hospital, and floor
are we in or on?
Registration
1. Ask the patient to name 3 objects, repeat them aloud to the
patient, and ask the patient to say them again.
2. If the patient cannot recall the objects, repeat them back until
the patient learns all 3. Count the number of trials and record:
_____
5
(1 for each correct
answer)
3
(1 for each correct
answer)
Attention and calculation
1. Have the patient recite serial 7s, to 35.
2. Alternatively, have the spell “world” backward.
Recall
Ask the patient to name the objects from the registration task.
Language
5
(1 for each correct
answer)
3
(1 for each correct
answer)
1. Show the patient a pencil and a watch and ask what they are.
2. Say “No ifs, ands, or buts" and ask the patient to repeat it.
9
(1 for each correct
3. Ask the patient to follow a 3-stage command: "Take a piece of
response)
paper in your right hand, fold it in half, and put it on the floor."
4. Ask the patient to follow 3 single commands: “Close your
eyes,” “Write a sentence,” and “copy this design” (after showing
the patient a design of intersecting pentagons).
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6
Source.—Adapted from Folstein and Folstein, 1975.
Note.— A score of <20 indicates dementia. Patients with the benign forgetfulness of
senility generally have a score of >25. Also assess the patient's level of consciousness
along a continuum: alert, drowsy, stuporous, comatose.
Causes: The cause of AD is unknown. The prevalent notion is that most cases of AD
are caused by converging risk factors that include advancing age, head injury, and
lipoprotein E-epsilon 4 genotype (whereas lipoprotein E-epsilon 3 being is relatively
protective), among other risk factors that appear to trigger a pathophysiologic cascade
that, over decades, leads to dementia.
Familial forms of AD account for less than 7% of all cases of AD, with most cases being
sporadic (ie, not inherited). Four major loci s have been found to be responsible for AD:
(1) that for amyloid precursor protein (APP, on chromosome 21), (2) that for presenilin I
(on chromosome 14), (3) that for presenilin II (on chromosome 1), and (4) those for
candidate markers (on chromosomes 12 and 19) and other proposed markers. Many
have postulated that mutations alter the mechanisms by which APP is processed,
leading to the deposition and eventual fibrillar aggregation of the 40– to 43–amino acid
residue known as the beta-amyloid peptide. This beta-pleated peptide is postulated to
have neurotoxic properties and to lead to an incompletely understood cascade of events
resulting in neuronal death, synapse loss, and the formation of NFTs and SPs among
other lesions.
Considerable attention has been devoted to elucidating the composition of NFTs and
SPs to find clues about the molecular pathogenesis and biochemistry of AD. Since the
time of Alois Alzheimer, SPs have been known to include a starchlike (or amyloid)
substance, usually in the center of these lesions, which is surrounded by a halo or layer
of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia).
One of the most important advances in recent decades has been the chemical
characterization of this amyloid protein, the sequencing of its amino acid chain, and the
cloning of the gene encoding its precursor protein (on chromosome 21). These
advances have provided a wealth of information about the mechanisms underlying
amyloid deposition in the brain, including information about the familial forms of AD.
This information has helped in testing the as-yet unverified hypothesis that amyloid
deposition causes AD.
Attention has also been devoted to the mechanisms leading to the development of
NFTs, the main constituent of which is the microtubule-associated protein tau that is
hyperphosphorylated and that accumulates in the perikarya of large and medium
pyramidal neurons. Studies have shown that both exonic and intronic mutations of the
tau gene result not in AD but in familial frontotemporal dementia associated with
parkinsonism. So far, no tau mutations have been identified in AD. These mutations are
presumed to modify properties of the neuronal cytoskeleton, eventually leading to
neuronal dysfunction and death.
DIFFERENTIALS
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Alzheimer’s Disease
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Aphasia
Cortical Basal Ganglionic Degeneration
Dementia With Lewy Bodies
Dementia in Motor Neuron Disease
Frontal and Temporal Lobe Dementia
Lyme Disease
Neurosyphilis
Parkinson Disease
Parkinson-Plus Syndromes
Prion-Related Diseases
Thyroid Disease
Wilson Disease
WORKUP
Lab Studies:

Although laboratory workup should be done in any patient with a condition that
can cause cognitive impairment, it is not mandatory.

Current recommendations from the American Academy of Neurology include
measurement of the cobalamin level and a thyroid function screening test.
Additional investigations are left to the physician, to be tailored to the particular
needs of each patient.

Laboratory tests may include the following:
o
Evaluation of the complete blood cell count and cobalamin levels:
Abnormalities in these measurements require further workup to rule out
hematologic disease.
o
Screening of liver enzyme levels: Abnormalities in these measurements
require further workup to rule out hepatic disease.
o
Assessment of blood cortisol level: Abnormalities in this measurement
require further workup to rule out adrenal system disease.
o
Analysis of thyroid stimulating hormone (TSH) levels: Abnormalities in this
measurement require further workup to rule out thyroid disease.
o
Rapid plasma reagent (RPR) test: Abnormalities require further workup to
rule out syphilis.
Imaging Studies:
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
Brain MRI or CT: In assessing AD, brain MRIs or CT scans show diffuse cortical
and/or cerebral atrophy. These studies are also used to rule out other CNS
disease.

SPECT: Under most circumstances, SPECT is an optional study and not
considered mandatory for the routine workup of patients with typical
presentations of AD. SPECT is used in qualified cases, usually those involving
atypical presentations, such as language disorders (eg, progressive aphasia),
visuospatial dysfunction syndromes, or other conditions that may be confused
with cerebrovascular disease or other neurodegenerative conditions.
Other Tests:

EEG: Findings for AD and other dementias have been described (see

EEG in Dementia and Encephalopathy). EEG can help in ruling out other
diseases that cause dementia, such as prion-elated diseases (eg, CreutzfeldtJakob disease).

Tau protein test: Some advocate measuring levels of this protein, a constituent of
NFTs and amyloid protein (found in senile plaques among other lesions) in the
CSF to diagnose AD. However, this test should not be considered mandatory or
reliable, and its result cannot be considered a substitute for other findings in the
clinical diagnosis of AD, for several reasons, as follows:

o
Levels of tau protein overlap considerably in healthy elderly individuals, in
patients with a variety of neurodegenerative disorders, and in those with
AD, these levels are not useful as an unequivocal biologic marker of AD.
o
Commercially available tests to detect tau protein levels in the urine are
not reliable.
o
In addition, the role of this test is not unanimously accepted in the
diagnosis and management of AD. In addition, these tests have no
unanimously agreed upon role in the care of patients.
Genotyping for apolipoproteins: This test is a research tool that is helpful in
determining the risk of AD in populations, but it is of little if any value in making a
clinical diagnosis and developing a management plan in individual patients.
Procedures:

Lumbar puncture: Perform lumbar puncture in select cases to rule out conditions
such as normal-pressure hydrocephalus, neurosyphilis, neuroborreliosis, and
cryptococcosis.
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Histologic Findings: See Pathophysiology for a discussion of the salient
histopathologic features of AD.
TREATMENT
Medical Care: Therapeutic approaches to AD are based on developing theories of its
pathogenesis and on the need to alleviate its cognitive and behavioral manifestations.
The predominantly symptomatic approach preceded, by many decades, the more
recent interventions based on our improving understanding of the pathogenesis and
pathophysiology of AD.
To date, no interventions have been shown to convincingly prevent AD or slow its
progression. Medical treatments for AD include psychotropic medications and
behavioral interventions, cholinesterase inhibitors (ChEIs) and the avoidance of
centrally acting anticholinergic medications, N-methyl-D-aspartate (NMDA) antagonists,
and other and new therapeutic interventions.

Psychotropic medications and behavioral interventions
o A variety of behavioral and pharmacologic interventions can temporarily
alleviate clinical manifestations of AD, such as anxiety, agitation,
depression, and psychotic behavior, which are best approached
symptomatically. These interventions are useful in managing AD, though
their effectiveness is often modest and temporary, and they do not prevent
the eventual deterioration of the patient's condition.
o Behavioral interventions range from patient-centered approaches to
caregiver training to help manage cognitive and behavioral manifestations
of AD. These interventions are often combined with the more widely used
pharmacologic interventions, such as anxiolytics for anxiety and agitation,
neuroleptics for aberrant and/or socially disruptive behavior, and
antidepressants or mood stabilizers for mood disorders and specific
manifestations (eg, episodes of anger or rage).
o No specific agent or dose of individual agents is unanimously accepted for
the wide array of clinical manifestations. At present, the US Food and
Drug Administration (FDA) has not approved any agent for the treatment
of AD. However, medications that many practitioners prefer are
haloperidol, risperidone, olanzapine, and (more recently) quetiapine. The
general recommendation is to use such agents as infrequently as possible
and at the lowest doses possible to minimize adverse effects, particularly
in frail, elderly patients.
o Particular concern has been raised about the potential for dopaminedepleting agents to aggravate the manifestations of dementia with cortical
Lewy bodies (DCLB), also known as Lewy body dementia (LBD), because
patients with DCLB may be extremely sensitive to these agents. Adverse
reactions to conventional neuroleptics have fueled the search for new
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o

Cholinesterase inhibitors
o A strategy widely used to address the symptoms of AD is palliating the
deficiency in cholinergic innervation to the cerebral cortex. Numerous lines
of evidence indicate that the corticipetal cholinergic system is targeted
relatively early and more or less selectively in AD. For over 2 decades, AD
has been characterized by substantial loss of acetylcholine (ACh) in the
cerebral cortex, progressive decline in cortical levels of choline
acetyltransferase (biosynthetic enzyme necessary for the synthesis of
ACh), and severe loss of neurons in the subcortical cholinergic nuclei that
project to the cerebral neocortex (ie, basal nucleus of Meynert) and
hippocampus (ie, medial septal nuclei).
o These observations have led to the theory that some of the clinical
manifestations of AD are due to loss of the cholinergic innervation to the
cerebral cortex. In turn, this theory led to development of an increasing
number of compounds capable of palliating the cholinergic defect by
interfering with the degradation of ACh by acetylcholinesterase (AChE),
the synaptic, or specific, form of cholinesterase. More recent compounds
include substances capable of blocking the nonsynaptic, or nonspecific,
cholinesterases; these are frequently called butyrylcholinesterases
(BuChEs).
o
An often neglected aspect of palliation of cholinergic deficits is the
avoidance of centrally acting anticholinergic medications. Patients not
uncommonly receive both ChEIs and anticholinergic agents, which negate
or at least counteracting the effects of the former. Therefore, a careful
listing of the patient's medications is important to reduce the doses of, or
ideally eliminate, all centrally acting anticholinergic agents.
See also the
o
Medication section below.
o

agents that alleviate disruptive behavior while minimizing the occurrence
of extrapyramidal manifestations and worsening of motor and behavioral
performance, which is frequently observed in DCLB. This is the basis for
the recent trend to use new-generation agents to alleviate the behavioral
manifestations of AD, with therapy usually extending into the more
advanced stages of the disorder.
Results of several studies indicate that anticonvulsants (eg, gabapentin)
may have a role in the treatment of behavioral problems in patients with
AD.
N-methyl-D-aspartate antagonists: A relatively new category of drugs, NMDA
antagonists, is based on an entirely different mechanism of action. Memantine is
the first NMDA antagonist approved in the United States. This agent is approved
for treating the advanced stages of AD, in contrast with ChEIs, which are
approved for only the early and intermediate stages. Of interest, memantine may
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

also be helpful in other neurodegenerative conditions, such as Huntington
disease, AIDS-related dementia, and vascular dementia.
Antidepressants: The role of antidepressants in the treatment of mood disorders,
and especially depression, cannot be overemphasized. Depression is observed
in more than 30% of patients with AD, and it frequently begins before AD is
clinically diagnosed. Therefore, palliation of this frequent comorbid condition can
considerably improve their cognitive and noncognitive performance. Other mood
modulators, such as valproic acid, can be helpful for the treatment of disruptive
behaviors and outbursts of anger, which patients with moderately advanced or
advanced stages of AD may have.
Other and new therapeutic interventions: Other agents proposed for the
treatment of AD and new drugs being developed are free-radical scavengers,
and estrogen- or selective estrogen-receptor agonists, anti-inflammatories, and
clioquinoline and other drugs.
o
o
o
The proposal that oxidative stress causes AD and evidence suggesting
that estrogen has a trophic effect on certain neuronal populations that is
lost after menopause were the bases for previous recommendations to
give high doses of tocopherol (1000 IU PO bid) to all patients and
estrogen replacement therapy to postmenopausal women with AD.
Federal and institutional policies do not mandate use of these agents; their
common use reflects the widespread belief that they may be beneficial.
Because findings show that estrogen supplementation may be associated
with cognitive impairment and that high-dose tocopherol may cause
adverse cardiovascular events, the entire body of evidence is being reevaluated, and few (if any) now recommend these treatments. Results to
date indicate that patients with clinical dementia do not benefit from
estrogen replacement therapy.
An additional treatment, the use of anti-inflammatory agents, is based on
the postulation that inflammation is needed for many AD lesions,
especially SPs, to develop and progress through the theoretical stages of
increasing severity. This theory has received considerable support, and
many studies purportedly show improvement or a lack of progression of
the manifestations of AD over relatively short periods of anti-inflammatory
therapy. No present recommendations require the use of antiinflammatories in AD; results of large-scale trials still underway have not
been published.
New drugs under development include clioquinoline, an antibiotic that may
help reduce brain amyloid deposition in patients with AD. Other, unrelated
compounds under development and are also expected to reduce or
eliminate cerebral amyloid deposition and possibly NFTs.
Surgical Care: No accepted surgical treatments exist for AD. One unconfirmed
postulate was that omental transposition to the brain may be beneficial in AD, but most
experts remain highly skeptical of this claim. Potential surgical treatments in the future
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may include the use of devices to infuse neurotrophic factors, such as growth factors, to
palliate AD. Studies are also underway to evaluate a claim that ventriculoperitoneal
shunting of CSF may be beneficial in AD.
Diet: No special dietary considerations exist for AD.
Activity:


Both physical and mental activities are recommended for patients with AD. Many
experts recommend mentally challenging activities, such as doing crossword
puzzles and brainteasers, both to prevent deterioration and to slow its rate.
o
The mental activities should be kept within a reasonable level of difficulty
for the patient, they should preferably be interactive, and they should be
designed to allow the patient to recognize and correct mistakes.
o
Most important, these activities should be administered in a manner that
does not cause excessive frustration and that ideally motivates the patient
to engage in them frequently.
o
Unfortunately, little standardization and rigorous testing has been done to
validate this treatment modality.
Some investigators have attempted various forms of cognitive retraining, also
known as cognitive rehabilitation. The results of this approach remain
controversial, and a substantial experimental study must still be performed to
determine if it is useful in AD.
MEDICATION
The mainstay of therapy is the use of centrally acting cholinesterase inhibitors to palliate
the depletion of ACh in the cerebral cortex and hippocampus. Because the clinical
manifestations of AD are believed to be partly due to a loss of the cholinergic
innervation to the cerebral cortex, compounds have been developed to palliate the
cholinergic defect by interfering with the degradation of ACh by AChE, the synaptic (or
specific) form of cholinesterase. Some of the more recently available compounds are
substances that inhibit also the nonsynaptic (or nonspecific) cholinesterases, which are
frequently called BuChE.
AChE inhibitors approved by the FDA for use in the early and intermediate stages of AD
are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine
(galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit
BuChE. This may be important for their therapeutic efficacy because BuChE levels
increase during the course of AD and are present in some AD lesions, including senile
plaques. At present, tacrine, is used seldom if at all because it has been superseded by
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the other 3. To date, the ChEIs is the only class of drugs that has been formally
approved for use in AD.
An increasing number of clinical studies demonstrate that cholinesterase inhibition can
have modest but detectable effects, such as improvement in cognitive performance, as
measured by tools such as the Alzheimer's Disease Assessment Scale-cognitive
subscale (ADAS-cog). More recent evidence indicates that ChEIs may also alleviate the
noncognitive manifestations of AD. For example, they can ameliorate behavioral
manifestations, as assessed by using tools such as the Neuropsychiatric Inventory, and
they may improve the performance of activities of daily living, as evaluated by using the
Progressive Deterioration Scale.
In general, the benefits are temporary because ChEIs do not address the underlying
cause of the degeneration of cholinergic neurons, which continues during the disease.
Although the increasingly large family of ChEIs was originally expected to help in only
the early and intermediate stages of AD, results indicate that (1) they improve cognitive
performance in advanced stages; (2) they significantly improve behavioral
manifestations (eg, wandering, agitation, socially inappropriate behavior associated with
advanced stages); and (3) they help in patients with presumed vascular components
added to dementia due to AD, as well as in patients with the DLB, which often co-occurs
or overlaps with AD (Lewy body variant of AD).
Therefore, the modest benefits of ChEIs seem to extend beyond the low-level cognitive
impairment in the early stages of AD. This phenomenon has not been fully explained.
Interesting speculations, which remain to be tested experimentally, include the
possibility that some of the newly recognized benefits in advanced behavioral and
cognitive performance may be associated with the inhibition of BuChE, in addition to
AChE, a characteristic of only some ChEIs currently in use.
The ChEIs share a common profile of adverse effects, the most frequent of which are
nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be
mitigated with slow uptitration to the desired maintenance dose. Use of drugs whose
absorption peaks are blunted by food (eg, rivastigmine) can further mitigate adverse
effects and improve the tolerability of ChEI treatment.
It may be reasonable to perform serial trials of different individual ChEIs when
effectiveness of 1 medication decreases or if adverse effects are not tolerable. A new
agent in this class should be tapered up when one switches among ChEIs, with the
understanding that cognition and/or behavior may temporarily worsen during this period.
No current evidence supports the use of more than 1 ChEI at a time. Another important
clinical caveat is that, once a ChEI is started, it should be continued indefinitely.
Stopping the medication may precipitate an acute, and possibly severe, cognitive and
behavioral decline that may not be resolved by restarting the ChEI. The cause for this
potentially catastrophic decline is not known.
FOLLOW-UP
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Patient Education:

Some investigators have postulated that education has a protective effect against
AD. They state that individuals with low levels of education and mental and/or
intellectual activity are said to be at increased risk for AD and to have a low
functional reserve to offset the cognitive and behavioral effect of AD. These
notions must be subjected to rigorous scientific assessment both to assess their
validity and, if true, to design cognitive and behavioral interventions to palliate
AD.

Patients with dementia, in general, and those with AD, in particular, usually have
a progressive deterioration in their behavior, cognition, and ability to perform
activities of daily living.

o
These changes may result in patients making inappropriate or adverse
psychosocial decisions, such as the mismanagement of funds or serious
lapses in their family, social, and occupational responsibilities.
o
Medical advice should include a warning about these possibilities, given to
both the patient and to their caregivers (at least those most directly
responsible for the patient's care) to minimize the risk of adverse legal
effects on the patient or others.
Particular attention should be given to the need to make a legal statement about
the patient's competency to handle his or her affairs and about assigning power
of attorney for the patient's estate and other matters. These delicate decisions
must be individualized and coupled with an attorney's advice.
REFERENCES:
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Alzheimer A: Uber eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat
1907; 64: 146-8.
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Braak H, Braak E, Grundke-Iqbal I, et al: Occurrence of neuropil threads in the
senile human brain and in Alzheimer's disease: a third location of paired helical
filaments outside of neurofibrillary tangles and neuritic plaques . Neurosci Lett
1986 Apr 24; 65(3): 351-5
Braak H, Braak E: Ratio of pyramidal cells versus non-pyramidal cells in the
human frontal isocortex and changes in ratio with ageing and Alzheimer's
disease. Prog Brain Res 1986; 70: 185-212/
Crook R, Verkkoniemi A, Perez-Tur J, et al: A variant of Alzheimer's disease with
spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1
. Nat Med 1998 Apr; 4(4): 452-5/
Crystal HA, Horoupian DS, Katzman R, et al: Biopsy-proved Alzheimer disease
presenting as a right parietal lobe syndrome . Ann Neurol 1982 Aug; 12(2): 1868/
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Alzheimer’s Disease
15
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Du Y, Dodel R, Hampel H, et al: Reduced levels of amyloid beta-peptide antibody
in Alzheimer disease. Neurology 2001 Sep 11; 57(5): 801-5/
Folstein MF, Folstein SE, McHugh PR: "Mini-mental state". A practical method for
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12(3): 189-98/
Frisoni GB, Padovani A, Wahlund LO: The diagnosis of Alzheimer disease before
it is Alzheimer dementia. Arch Neurol 2003 Jul; 60(7): 1023; author reply 1023-4/
Gilman S, Koller M, Black RS, et al: Clinical effects of A{beta} immunization
(AN1792) in patients with AD in an interrupted trial. Neurology 2005 Apr 7;/
Hamdy RC: Alzheimer's disease: an overview. South Med J 2001 Jul; 94(7): 6612/
Hof PR, Morrison JH: The cellular basis of cortical disconnection in Alzheimer's
disease and related dementing conditions. In: Terry RD, Katzman R, Bick KL,
eds. Alzheimer's Disease. New York: Lippincott Raven; 1994: 197-229.
Irizarry MC, Hyman BT: Alzheimer disease therapeutics. J Neuropathol Exp
Neurol 2001 Oct; 60(10): 923-8/
Jonsson L, Jonsson B, Wimo A, et al: Second International Pharmacoeconomic
Conference on Alzheimer' s Disease . Alzheimer Dis Assoc Disord 2000 Jul-Sep;
14(3): 137-40/
Katzman R: Alzheimer's disease . N Engl J Med 1986 Apr 10; 314(15): 964-73/
Kuljis RO: Lesions in the pulvinar in patients with Alzheimer's disease . J
Neuropathol Exp Neurol 1994 Mar; 53(2): 202-11/
Kuljis RO: Modular corticocerebral pathology in Alzheimer's disease. In:
Mangone CA, Allegri RF, Ariza, eds. Dementia: A Multidisciplinary Approach.
1997: 143-55.
Maelicke A, Albuquerque EX: Allosteric modulation of nicotinic acetylcholine
receptors as a treatment strategy for Alzheimer's disease. Eur J Pharmacol 2000
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25; 341(22): 1670-9/
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Florida Heart CPR*
Alzheimer’s Disease
16
Florida Heart CPR*
Alzheimer’s Assessment
1. Alzheimer’s disease affects approximately how many people in the United
States?
a. 5 million
b. 10 million
c. 16 million
d. 22 million
2. What does the pathology of AD include at the microscopic level?
a. Neurofibrillary tangles and senile plaques
b. Plaques on the myelin sheath
c. Abnormal levels of serotonin
d. None of the above
3. Alzheimer’s can be assessed using a
a. Biopsychosocial exam
b. Mini mental status exam
c. Interpersonal assessment with a physician
d. blood test
4. Alzheimer’s disease is caused by:
a. Genetic factors
b. Environmental factors
c. A prior bacterial infection
d. AD is idiopathic
5. AD treatments include:
a. Surgical intervention
b. Pharmacological intervention
c. Diet and exercise
6. The MMSE (Mini Mental Status Exam) assesses: orientation, registration,
attention and calculation, and ______.
a. Emotion
b. Cognition
c. Language
d. Problem solving
7. The earliest evidence of AD is the onset of _____________ memory loss that is
_______ over several years.
a. Recurring/remissive; variably progressive
b. chronic, insidious; slowly progressive
Florida Heart CPR*
Alzheimer’s Disease
17
c. recurring/remising; rapidly progressive
d. chronic, insidious; moderately stable
8. Common neurologic symptoms other than memory loss include:
a. Aphasia
b. Impaired visuospatial skills
c. Impaired executive function
d. All of the above
9. Clinical manifestations of AD include:
a. Anxiety
b. Depression
c. Psychotic behavior
d. All of the above
10. In general, the benefits of cholinesterase inhibition are temporary because:
a. The body builds up a tolerance for the drug
b. ChEIs produce severe side effects when taken for extended periods of time
c. ChEIs do not address the underlying cause of the degeneration of cholinergic
neurons, which continues during the disease.
d. The considerable costs of ChEIs are often too great for patients to sustain
Florida Heart CPR*
Alzheimer’s Disease