Download The pathophysiology of Alzheimer`s disease

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THE PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE
AND DIRECTIONS IN TREATMENT
—
Ann S. Morrison, PhD, RN, CS,* and Constantine Lyketsos, MD, MHS†
ABSTRACT
The pathophysiology of Alzheimer’s disease
(AD) is complex, involving several neurotransmitter systems and pathophysiologic processes. The 3
hallmarks of AD—β-amyloid plaques, neurofibrillary tangles, and neuronal cell death—are well
known and central factors in AD pathology. These
hallmarks, combined with our information on neurotransmitter involvement, are specific to AD
based on the timing, sequence, and location of
these changes. This article reviews the pathophysiology and course of brain damage seen during
AD progression, from preclinical to severe stages.
Understanding these processes is fundamental in
understanding AD progression and symptom
manifestation, and in assessing the potential risks
and benefits of therapeutic interventions. There
are now 5 approved drugs for the cognitive symptoms of AD—4 acetylcholinesterase inhibitors
(approved for mild to moderate AD) and 1 noncompetitive glutamate receptor antagonist
(approved for moderate to severe AD). Recent
studies with these drugs are focusing on longerterm follow-up (1 year and beyond), in addition to
more “clinically relevant” outcomes, such as
measures of function and nursing home
*Clinical Nurse Specialist Coordinator, Department of
Psychiatry, Alzheimer’s Disease Research Center, The Johns
Hopkins Hospital, Baltimore, Maryland.
†Professor of Psychiatry and Behavioral Sciences,
Codirector, Division of Geriatric Psychiatry and
Neuropsychiatry, The Johns Hopkins Hospital, Baltimore,
Maryland.
Address correspondence to: Ann S. Morrison, PhD, RN,
CS, Clinical Nurse Specialist Coordinator, Department of
Psychiatry, Alzheimer’s Disease Research Center, The Johns
Hopkins Hospital, 550 Broadway Avenue, Baltimore, MD
21205. E-mail: [email protected].
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placement. Other treatments (vitamins E and/or
C, nonsteroidal anti-inflammatory drugs, and
statins [cholesterol-lowering drugs]) show some
promise in preventing or delaying AD progression, although more data are needed. There are
now several published guidelines for the treatment of AD. Although some may argue that the
effect of these drugs is modest, any preservation
of function and delay of nursing home placement
has important and permanent consequences for
the patient and caregiver. The profound and
sometimes rapid loss of memory and function
with AD underscores the importance of trying at
least 1 of these treatments in a patient with AD.
(Adv Stud Nurs. 2005;3(8):256-270)
ALZHEIMER’S DISEASE PATHOPHYSIOLOGY
CHANGES IN BRAIN STRUCTURE
Alzheimer’s disease (AD) pathology can be characterized on a macro level as the progressive loss of brain
tissue. As the disease progresses, neurons die in a particular pattern over time. One of the earliest signs of
AD is memory loss, particularly short-term recall. The
brain areas involved in memory include the cortex,
especially the hippocampus (Figure 1).1 Preclinical AD
begins in the entorhinal cortex, which connects the
hippocampus, the structure responsible for memory
formation (short- and long-term memory; Figure 2),
to the cerebral cortex.1 Several studies, such as ones
including magnetic resonance imaging, suggest that
neuronal loss (measured by atrophy in select regions)
may start years before signs of memory loss emerge.2,3
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Figure 2. Brain Changes in Preclinical Alzheimer’s
Disease
Figure 1. Major Areas of the Brain
Corpus Callosum
Cerebral Cortex
Thalamus
Cerebral
Cortex
Hypothalamus
Hippocampus
Cerebellum
Brain Stem
Hippocampus
Side view of the brain
Entorhinal
Cortex
Reprinted with permission from Alzheimer’s Disease Education and Referral
Center Web site. Available at: http://www.alzheimers.org/unraveling/04.htm.
Accessed June 17, 2005.1
Copyright ©2002, Christy Krames.
As the brain atrophies, cerebrospinal fluid fills in the
space previously occupied by brain tissue.
In mild to moderate AD, patients experience more
prominent memory loss (eg, difficulty recalling wellknown names and confusion about familiar places), a
decline in the ability to process complex thoughts (eg,
difficulty with balancing the checkbook or preparing a
meal), and mood and personality changes. In the
brain, atrophy extends to other areas of the cerebral
cortex (Figure 3).1
At the later stages of AD progression, the cortex has
atrophied in areas that control speech, reasoning, sensory processing, and conscious thought (Figure 4).1,4 As
expected with this degree of brain atrophy, the symptoms of severe AD increase in severity (ie, impaired longterm memory, seizures, incontinence, weight loss, no
recognition of loved ones, inability to sit up, and groaning/moaning/grunting). The progression of atrophy
throughout the brain is diagrammed in Figure 5.1
DEGENERATIVE PROCESSES IN ALZHEIMER’S DISEASE
On a micro level, AD is characterized by 3 neuropathologic hallmarks: extracellular plaques of β-amyloid protein (amyloid plaques), intracellular
neurofibrillary tangles (NFTs), and neuronal degeneration. Plaques and NFTs were first discovered by Alois
Alzheimer in a 1906 autopsy of a demented patient.
Although they are a defining component of AD, they
are not unique to AD. Plaques and NFTs occur with
normal aging and in some other neurodegenerative disorders. In AD, plaques and NFTs are localized to areas
in the brain that correspond to clinical symptoms.
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Figure 3. Brain Changes in Mild to Moderate
Alzheimer’s Disease
Cortical
Shrinkage
Moderately
Enlarged
Ventricles
Shrinkage of
Hippocampus
Reprinted with permission from Alzheimer’s Disease Education and Referral
Center Web site. Available at: http://www.alzheimers.org/unraveling/04.htm.
Accessed June 17, 2005.1
Figure 4. Brain Changes in Severe Alzheimer’s
Disease
Extreme Shrinkage of
Cerebral Cortex
Severely
Enlarged
Ventricles
Extreme
Shrinkage of
Hippocampus
Reprinted with permission from Alzheimer’s Disease Education and Referral
Center Web site. Available at: http://www.alzheimers.org/unraveling/04.htm.
Accessed June 17, 2005.1
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Figure 5. Brain Damage and Atrophy During Alzheimer’s
Disease Progression
A
B
C
A, preclinical Alzheimer’s disease; B, mild to moderate Alzheimer’s disease; and
C, severe Alzheimer’s disease.
Reprinted with permission from Alzheimer’s Disease Education and Referral Center
Web site. Available at: http://www.alzheimers.org/unraveling/04.htm. Accessed June
17, 2005.1
β-amyloid plaques are thought to play the central
role in AD pathogenesis (the “amyloid hypothesis”),
with several diverse pathophysiologic processes that
follow (Figure 6), described as an “amyloid cascade.”5
The AD pathophysiologic cascade is complicated, but
each discovery of a neurotransmitter or pathologic
process leads to the potential discovery of new therapeutic targets.
The β-amyloid hypothesis
β-amyloid plaques are clumps of insoluble peptides
that result from the abnormal cleavage of amyloid precursor protein (APP), the exact function of which is
unknown. APP is normally cleaved by 3 enzymes—βsecretase, γ-secretase, and α-secretase. Cleavage by βsecretase, followed by γ-secretase, yields a soluble 40
amino acid peptide (Figure 7).1 In AD, a variant form
of the γ-secretase cleaves APP at an incorrect place,
creating a 42 amino acid peptide called Aβ42 or Aβ,
which is not soluble and aggregates into identifiable
clumps termed β-amyloid plaques (Figure 8).1 α-secretase actually serves a protective function as it cleaves
APP at a site that prevents Aβ formation.
Genetic studies of AD support the role of γ-amyloid plaques and β-secretase in AD pathogenesis.
Three genes have been identified in familial AD (APP,
PS1 [presenilin 1], and PS2) and all are known to be
involved with the formation of Aβ. (The use of italics
indicates a gene, whereas normal font indicates the
protein made from the gene.) APP is the gene that
codes for APP (the protein) and is located on chromosome 21. Interestingly, people with Down’s syndrome
(trisomy 21—3 copies of chromosome 21) ultimately
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develop AD at a younger age than the general population.6 PS1 and PS2 are genes that code for presenilin,
the catalytic subunit of γ-secretase. There are at least
20 known mutations of APP, more than 140 known
mutations in PS1, and approximately 10 in PS2.6,7
Immunization against Aβ is under investigation as a
treatment in animals and humans.8-11
Neurofibrillary tangles are seen as dying or dead
neurons when viewed after histologic staining. NFTs
result from the destruction of neuronal microtubules
caused by the modification of their supporting protein, tau (Figure 9).1 Microtubules are essential components of neuronal cell structure; they act as tracks
along which nutrients are delivered and neuronal
transmission is propagated in the neuronal axon.
During AD pathogenesis, tau proteins become hyperphosphorylated, disrupting their bonds to microtubules, thus collapsing microtubule structure and
Figure 6. Diagram of the Amyloid Cascade
Cytoplasm
γ-secretase
γ-secretase
Cell
membrane
α-secretase
p3
Extracellular
space
Aβ
β-secretase
APP
β-APP
α-APP
Aβ generation
Oxidation
Excitotoxicity
Aβ aggregation Inflammation
Tau hyperphosphorylation
Neuron
Senile plaque with
microglial activation
Cell
death
Neurofibrillary
tangles
Cognitive
and behavioral
abnormalities
Neurotransmitter
deficit
APP = amyloid precursor protein.
Reprinted with permission from Cummings. N Engl J Med. 2004;351:56-67.5
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destroying the neuron’s transport and communication
system. Neuronal cell death ensues. Although the
causal relationship is unclear, hyperphosphorylation of
tau is thought to occur after plaque formation.12,13
The cholinergic hypothesis
Loss of cholinergic neurons is another well-established pathology of AD. By late-stage AD, the number
of cholinergic neurons is dramatically reduced; in
some parts of the brain there is more than 75% loss.14
Acetylcholine is an important neurotransmitter in
brain regions involving memory, and loss of cholinergic activity correlates with some aspects of cognitive
impairment. Cholinergic abnormalities are the most
prominent neurotransmitter changes in AD.
Acetylcholine binds to 2 postsynaptic receptor
types: muscarinic and nicotinic. Presynaptic nicotinic
receptors influence the release of neurotransmitters
important for memory and mood—acetylcholine, glutamate, serotonin, and norepinephrine—all of which
have been implicated in AD pathology.
The glutamatergic/excitotoxicity hypothesis
Glutamate is the primary excitatory neurotransmitter in the brain. In the central nervous system, it is
virtually ubiquitous and is estimated to be involved in
roughly 66% of all brain synapses.15,16 Glutamatergic
neurons are also critical because they form projections
to other areas of the brain, including cholinergic neurons, thus influencing cognition. In AD, the pathology associated with glutamatergic neurons is not with
glutamate itself but with the levels of pre- and postsynaptic glutamate receptors. Of the 3 types of postsynaptic glutamate receptors, AD pathology has only
been linked to 1 type, the N-methyl-D-aspartate
(NMDA) receptor, which appears to undergo sustained low-level activation in AD brains, causing sustained low-level neurotransmission. This dysregulation
at the glutamate NMDA receptor is thought to perpetuate a vicious cycle of neuronal damage, in which
continuous activation of the receptor leads to chronic
calcium influx within the neuron that interferes with
normal signal transduction.17 It also leads to increased
production of APP, which, as noted earlier in this article, is associated with higher rates of plaque development and hyperphosphorylation of tau protein (thus
NFT formation) followed by neuronal toxicity.18-21
Glutamate is cleared from the synapse by reuptake into
the nerve terminal and surrounding glial cells.
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Figure 7. The Structure of Amyloid Precursor
Protein Relative to the Cell Membrane
β-amyloid
Enzymes
Amyloid precursor protein is a transmembrane protein. Cleavage by β-secretase, followed by γ-secretase, yields a soluble 40 amino acid peptide. This
peptide is shown here in green.
Copyright ©2002, Christy Krames.
Figure 8. Insoluble Aggregates of Aβ42
β-amyloid
Plaque
Copyright ©2002, Christy Krames.
Figure 9. The Role of Tau Protein in Neuronal Cell
Death
Stabilizing
Tau Molecules
Healthy Neuron
Microtubules
Disintegrating
Microtubule
Microtubule Subunits
Fall Apart
Tangled Clumps
of Tau Proteins
Diseased Neuron
Disintegrating
Microtubules
Copyright ©2002, Christy Krames.
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Dementia patients also appear to have reduced numbers of glutamate reuptake sites or abnormal expression of a glutamate transporter, which may be linked
to NFT formation.22,23
nases COX-1 and COX-2, in the AD brain.28 It is interesting to note that the inflammation in AD is chronic
and localized to discrete areas of the brain, as are the
other types of cellular damage with AD.29
The oxidative stress hypothesis
In AD brains, Aβ induces lipid peroxidation and
generates reactive oxygen and nitrogen species; these
are oxygen or nitrogen molecules containing an
unpaired extra electron (termed species) that reacts
with other molecules to achieve a stable configuration.
During this process, the reactive species forms a molecular bond with another molecule, while a high-energy electron (termed a “free radical”) is thrown off. The
reaction is permanent, thus structurally and functionally altering the molecule to which the reactive species
is attached. The free radical is left to cause cellular and
molecular damage. This oxidative damage can occur in
virtually all types of neuronal macromolecules (eg,
lipids, carbohydrates, proteins, and nucleic acids). The
brain is especially vulnerable to damage from oxidative
stress because of its high oxygen consumption rate,
abundant lipid content, and relative paucity of antioxidant enzymes compared to other organs. In neurons,
oxidation can result in numerous problems, including
upregulation of proinflammatory cytokines and
irreparable DNA damage.24,25 Oxidative stress is
thought to be important early in AD progression
because it is temporally linked to the development of
plaques and NFTs.26
Other neurotransmitter deficiencies
During the AD process, brain regions in which
acetylcholine, serotonin, and norepinephrine are
prominent become altered, affecting widespread
areas of the cerebral cortex. Serotonin is known to be
important in affective illness (eg, depression and anxiety), and depression is a common comorbidity with
AD. The number of serotonin receptors and transporters are altered in AD brains, corresponding to
decline in measures of cognition and presence of anxiety.30-32 Also, norepinephrine levels are reduced and
norepinephrine neurons are lost in AD.33
Norepinephrine may play an important role in some
of the behavioral and psychological symptoms of
dementia (aggression, agitation, and psychosis), in
addition to memory loss.34
The chronic inflammation hypothesis
β-amyloid deposits, NFTs, and damaged neurons
may stimulate inflammation as a natural response to
cell damage. Microglia (1 of 4 types of brain cells,
including neurons, astrocytes, and oligodendrocytes)
are involved in immune and inflammatory responses
to injury or infection within the brain. During AD
pathogenesis, microglia are activated to release potentially cytotoxic molecules, such as proinflammatory
cytokines, reactive oxygen species, proteinases, and
complement proteins.27 This is a normal response to
cellular damage that, in AD, appears to proceed uninhibited, causing more harm than protection. Cytokines
stimulate inflammatory processes that may promote
apoptosis (programmed cell death) of neurons and oligodendrocytes and induce myelin damage. Inflammation
as part of AD pathology has been observed as increased
prostaglandins, which are produced by the cyclooxyge-
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Cholesterol
Cholesterol is also now thought to be involved in
AD pathogenesis. The brain contains the highest
amount of cholesterol of any human organ.35
Elevated cholesterol levels appear to increase Aβ production, whereas reduced cholesterol synthesis (eg, as
a result of statin drugs) reduces Aβ levels, thus the
risk of AD progression.36 Cholesterol reduction may
also reduce the risk or severity of dementia through
protection from vascular risk factors; vascular dementia often coexists in patients with AD. In the
Honolulu-Asia Aging Study, cholesterol levels of 218
Japanese-American men were measured at mid-life
and late-life. At autopsy, there was a strong linear
association between mid-life and late-life high-density lipoprotein cholesterol and the number of plaques
and NFTs in the cortex.37
SUMMARY
Our understanding of AD pathology is now
extending beyond the details of pathophysiologic
processes to a broader view of the sequence and timing of these events in the development of symptoms
and illness progression. Aβ generation is considered
to be the first step of an “amyloid cascade,” which
continues with oxidation, excitotoxicity, inflammation, and the hyperphosphorylation of tau. Each of
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these processes contributes to neurotransmitter
abnormalities and neuronal cell death, which then
manifest as cognitive and behavioral abnormalities.5
KEY POINTS
• In AD, brain atrophy and neuronal loss occur in
a predictable pattern beginning with the entorhinal cortex and hippocampus, ultimately progressing throughout the brain.
• AD is characterized by 3 neuropathologic hallmarks: plaques of β-amyloid protein (amyloid
plaques), NFTs, and neuronal degeneration, all
of which occur during normal aging, but in AD
occur in specific locations in the brain.
• β-amyloid plaques are thought to play the central
role in AD pathogenesis, described as the “amyloid cascade.”
• The β-amyloid hypothesis maintains that formation of β-amyloid plaques is the first step in AD
pathology, and genetic and histopathologic studies support this hypothesis. NFTs occur after
plaque formation.
• The cholinergic hypothesis is supported by the
drastic and widespread loss of cholinergic neurons in AD, the benefits with acetylcholinesterase
inhibitors, and the role of the nicotinic cholinergic receptor.
• The glutamate/excitotoxicity hypothesis maintains that slow but steady activation of a glutamate receptor leads to cellular damage.
• The oxidative stress hypothesis suggests that βamyloid induces oxidative stress causing permanent damage to some neuronal macromolecules
(especially lipids) and creating reactive species,
which further propagate neuronal toxicity.
• The chronic inflammation observed with AD is
thought to be the result of all of these mechanisms causing cell damage and death. In AD,
inflammatory cytokines respond to these processes and contribute to neuronal destruction
because they appear to act uninhibited.
• Serotonin and norepinephrine are also involved
in AD pathology. Serotonin is an important factor in depression and anxiety, both of which are
common in patients with AD.
• Cholesterol also appears to have a role in AD
progression, perhaps through a reduction in vascular risk factors, which are common in patients
with AD.
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TREATMENTS FOR ALZHEIMER’S DISEASE
OVERVIEW
Pharmacologic treatments for the primary symptoms of AD, namely memory loss and cognitive
impairment, have only become available within the
past decade. Four of 5 approved therapies (tacrine,
donepezil, rivastigmine, and galantamine) act by
inhibiting the enzyme acetylcholinesterase, which is
responsible for breaking down acetylcholine postsynaptically, thus keeping acetylcholine in the synapse
longer. As described earlier in this article, cholinergic
neuron loss is the primary type of neurodegeneration
in AD. The fifth drug, memantine, acts as a noncompetitive antagonist to the NMDA receptor, curtailing
the low-level but steady NMDA receptor activation
thought to occur in AD and contributing to excitotoxicity.17 Several other treatments that address not
only the symptoms but also the pathophysiologic
processes in AD are also under investigation.
CHOLINESTERASE INHIBITORS
Although there are 4 approved cholinesterase
inhibitors, only 3 are commonly used in the United
States. The fourth, tacrine, is still available but rarely
prescribed because of the potential hepatotoxicity
associated with its use; it also has a complicated titration schedule. Tacrine should probably never be recommended as first-line therapy for AD. Although it is
still on the market, there is no practical use for tacrine
in the treatment of AD. However, nurses may still
encounter prescriptions for it. A summary of the recommended dosing and titration schedule, in addition
to common adverse events with each drug, are listed in
Table 1.38-41 Donepezil, rivastigmine, and galantamine
are indicated for mild to moderate AD; memantine is
indicated for moderate to severe AD.
Donepezil was the first drug to be approved by the
US Food and Drug Administration (FDA) for the
symptoms of mild to moderate AD. Its efficacy was
established in 2 randomized, double-blind, placebocontrolled studies.42,43 Donepezil was followed by
rivastigmine, the clinical efficacy of which was shown
in 3 randomized, placebo-controlled studies in the
United States and internationally.44-46 The efficacy of
galantamine was demonstrated in 4 randomized, double-blind, placebo-controlled studies—2 in the United
States and 2 in other countries.47-50 The initial safety
and efficacy studies were typically shorter than 6
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Table 1. The Currently Available Treatments for AD Symptoms—A Summary*
Drug
Common Adverse Events†
AD Indication
Dosing
Donepezil
Mild to moderate
5 mg or 10 mg; treatment with a 10-mg dose
should not be considered until patients have been
on a daily dose of 5 mg for 4 to 6 weeks to avoid
adverse events
Nausea, diarrhea, insomnia, vomiting, muscle
cramps, fatigue, and anorexia
Rivastigmine
Mild to moderate
3–6 mg twice daily; starting dose: 1.5 mg twice daily;
increase to 3 mg twice daily after 2 weeks; other
dose increases should be separated by at least 2 weeks
Nausea, vomiting, loss of appetite, dyspepsia,
asthenia, and weight loss
Galantamine
Mild to moderate
8–12 mg twice daily, preferably with morning and
Nausea and vomiting
evening meals; 24 mg/d may provide additional
benefit for some patients, but it is associated with
more adverse events; starting dose: 4 mg twice daily;
increase to initial maintenance dose after at least 4 weeks
Memantine
Moderate to severe
Target dose: 20 mg/day; starting dose: 5 mg/day;
Confusion, dizziness, headache, and constipation
titration: increase in 5-mg increments to 10 mg/d (5 mg
twice daily), 15 mg/d (5 mg and 10 mg as separate
doses), 20 mg/d (10 mg twice daily); minimum
recommended interval between dose increases is
1 week; can be taken with or without food
*Tacrine continues to remain on the market, but it is rarely used because of its potential hepatotoxicity and other adverse events.
†Based on clinical studies.
AD = Alzheimer’s disease.
Data from Donepezil US prescribing information38; Galantamine US prescribing information39; Memantine US prescribing information40; Rivastigmine US prescribing information.41
months. Current studies of AD drugs are focusing on
longer follow-up, other AD-related indications (eg,
mild cognitive impairment [MCI] and more severe
stages of AD), nursing home placement, vascular risk
factors, and the pathophysiology of AD.
Long-term follow-up
There has been 1 long-term study of donepezil that
extended to 4.9 years, an extension of an original 14week study.42 The results showed evidence of clinical
benefit (ie, maintenance of baseline scores for cognition measures) during the first 6 to 9 months of openlabel treatment, with gradual cognitive decline after 9
months. The treatment group was compared to historical controls, which was a serious methodological
problem for this study. The rate of cognitive decline
throughout the nearly 5-year study was slower for
those patients receiving donepezil than the estimates
for patients who had not been treated.51 The benefits
with rivastigmine have been shown in studies of 1- and
2-years’ duration. In the 1-year studies, differences in
cognitive decline as measured by the AD assessment
scale-cognitive subscale were -4.45 ± 0.8 (placebo) ver-
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sus 0.82 ± 0.71 (rivastigmine) and -8.0 (historical placebo) versus -3.8 (rivastigmine).52,53 In the 2-year study, cognitive decline slowed by 35% in those patients receiving
rivastigmine compared to a historical placebo group.54
Improvement with rivastigmine was also observed in a
subgroup of moderately severe patients.55 The long-term
efficacy of galantamine was shown in 3 studies. In an
18.5-month study, patients taking galantamine enjoyed
sustained cognitive benefits during the entire study duration.56 In two 3-year studies, galantamine was associated
with a roughly 50% slower cognitive decline compared to
predicted rates of decline in a clinically similar historical
control sample of patients with AD.57,58
Disease severity
Donepezil has shown significant benefit on measures of cognition compared to placebo in patients
with “early stage” (mild) AD.59 An important observation in this study population is that the placebo group
showed virtually no signs of cognitive decline (as measured by the Mini-Mental State Examination
[MMSE]) during the study period, whereas in studies
of patients with mild to moderate AD, patients receiv-
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ing placebo showed cognitive decline in MMSE scores
during the study.59 Therefore, the extent of observed
donepezil benefit may depend on the level of AD
severity. At the other end of the severity spectrum,
donepezil was compared to placebo in patients with
moderate to severe AD and showed significant benefit
in cognition measures at all time points during the 6month study.60
Two studies have analyzed the effect of rivastigmine
based on disease severity, but from a different approach.
In a 1-year study, patients were classified as slowly progressive or rapidly progressive, based on the magnitude
of response seen in the first 6 months of the study. The
final results showed notable and significant differences in
response to rivastigmine between these 2 groups of
patients, with patients who were rapidly progressive
obtaining greater benefit from rivastigmine treatment.61
In a 12-month study of patients with mild AD or MCI,
cognitive function was slightly improved or maintained
in the patients with mild AD and unchanged or slightly
worsened in the patients with MCI (both groups receiving rivastigmine); cognitive function was markedly worsened in untreated patients with AD.62
Functional measures
Researchers are now turning to more “clinically relevant” outcomes, such as functional decline (ie, ability
to perform activities of daily living [ADLs] or instrumental ADLs [IADLs]), nursing home placement, and
effect on caregiver burden. ADLs focus on basic functioning, such as toileting, feeding, dressing, bathing,
walking, and grooming. IADLs are more complex
activities, which most adults of normal mental capacity can perform, such as operating household appliances, paying bills and managing money, shopping,
preparing meals, and participation in hobbies. The
effect on ADLs is important for several reasons. ADLs
instill and maintain a sense of independence and selfefficiency, which is critical for patients’ and caregivers’
quality of life. In AD, loss of ADLs is enduring and is
a significant predictor of institutionalization.63
Therefore, preservation of ADLs is a critical outcome
with important and permanent ramifications.
A 1-year study of donepezil versus placebo suggested that donepezil use may have effects on delaying loss
of ADLs. Patients taking donepezil were 31% less likely to experience functional decline (ie, losing the ability to perform an ADL or IADL) than those taking
placebo.64 The authors noted that patients on
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donepezil tended to stabilize over time, rather than to
improve over baseline, “suggesting that clinicians
should aim for stability rather than actual improvement in ADLs.”64 This is an important message to convey to patients and their caregivers as AD progresses
and they consider treatment with a cholinesterase
inhibitor. Another study showed not only slower
decline in ADLs and IADLs with donepezil treatment
but also less decline in the components required for
completing each ADL (initiation, planning and organization, and effective performance).65 Caregiver burden was also measured as time required with the
patient for ADLs/IADLs and stress levels. Caregivers
reported spending a mean of 52.4 fewer minutes/day
on ADLs and 17.2 fewer minutes/day on IADLs with
donepezil-treated patients. Almost all components of
the caregiver stress scale favored donepezil. The
authors also noted the importance of stabilizing cognitive function because the placebo group did not show
a floor effect (ie, patients never reached a point at
which further decline was not measurable).65
Rivastigmine has beneficial effects on ADLs, as
shown in a retrospective analysis of 3 studies.66 Also,
ADL impairment differed across the stages of AD.
Table 2 lists the ADLs with a significant change from
baseline based on 3 levels of severity.66
A secondary analysis of a 5-month study showed that
galantamine treatment resulted in little or no decline
from baseline in ADL measures compared to significant
decline in the placebo group.48,67 Galantamine treatment
resulted in maintenance or improvement in ADL and
IADL measures, with significant improvement over
placebo in 3 of 6 basic ADLs (toileting, bathing, and
grooming) and 6 of 17 IADLs (conversation, managing
personal belongings, current events, writing, hobbies,
and operating household appliances).67 ADL stabilization was seen throughout the range of AD severity, but
the greatest differences were observed in those patients
with severe disease.67
Regarding caregiver time, galantamine also has
notable effects. Pooled data from two 6-month studies
show that caregivers reported spending a mean of 32
fewer minutes per day with galantamine-treated
patients than with placebo-treated patients, a savings
of approximately 3.5 hours per week. In patients with
moderate AD, the benefits were even greater—a mean
daily time savings of 53 minutes or more than 6 hours
per week. Similarly, galantamine-treated patients could
spend 27 more minutes per day unsupervised and, in the
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moderate AD group, the benefit was extended to spending 68 more minutes per day unsupervised.68
The profound consequences of maintaining ADLs
is illustrated in a case study from Tariot and
Jakimovich, in which donepezil was administered to a
patient with severe AD, behavioral problems, and several comorbidities following admission to a long-term
care facility.69 The positive effects of donepezil treat-
Table 2. ADLs Affected Based on Degree of AD Severity with Rivastigmine or Placebo Treatment
GDS ≤3
GDS = 4
PDS Item
Mean change
Improvement, %
Mean change
Improvement, %
Cannot handle money
-0.1 vs -4.1*
49 vs 33*
Has a clear concept of time
0.1 vs -3.7
53 vs 40
Discusses politics
-0.1 vs -3.3
51 vs 38
Dresses properly
-0.5 vs -4.1
50 vs 39
Drives car safely
-1.9 vs -5.4
44 vs 33
Forgets things
0.9 vs -3.3*
Rearranges objects
Stops participation in family finances
Cannot tell time
0.5 vs -2.2
52 vs 40
Dials telephone numbers
2.1 vs -2.1
56 vs 44
Increased time doing hobbies/pursuits
2.4 vs -1.0
62 vs 43
Takes normal precautions
1.0 vs -1.7
56 vs 40
Unable to drive alone
1.3 vs -3.5
55 vs 42
GDS ≥5
Mean change Improvement, %
-1.6 vs -6.9
45 vs 32
52 vs 32*
-1.5 vs -5.3*
40 vs 28*
0.7 vs -2.3
51 vs 38
-1.1 vs -5.8*
45 vs 30*
-1.4 vs -4.7
45 vs 32
Cannot use telephone
-3.1 vs -7.6*
42 vs 30*
Confusion in different settings
-2.3 vs -6.5*
42 vs 28*
Good eating manners
-2.5 vs -6.7*
42 vs 28*
Makes mistakes doing hobbies/pursuits
-1.1 vs -6.8*
44 vs 27*
Does hobbies/pursuits
Stops household chores
Walks/travels alone
Tells time
Uses tools properly
Cannot discuss family finances
Walks safely
Cannot accurately care for finances
Stops social attendance
Drives own car
Works at his/her job
Meaningfully discusses TV, movies, and
similar events with spouse, family, or caregiver
This table shows the ADLs as listed in the PDS that were significantly changed from baseline during the study in the observed cases dataset. AD severity was measured
by the GDS and divided into 3 groups. As the GDS score increases, the severity of AD increases.
*Indicates P <.05 for rivastigmine versus placebo in the intent-to-treat dataset.
AD = Alzheimer’s disease; ADL = activity of daily living; GDS = Global Deterioration Scale; PDS = Progressive Deterioration Scale.
Reprinted with permission from Potkin et al. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:713-720.66
264
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ment included engagement in meaningful conversations about family events and current events seen on
television, although he was amnesic for details; coherent periods of (factually correct) reminiscence on his
life; and improved ability to perform ADLs, including
independent toileting, reduced belligerent and sexually inappropriate behavior, discontinuation of haloperidol, ability to travel to a family event, and restoration
of walking ability; none of which were possible when
he was admitted to the nursing facility.69
Nursing home placement
Nursing home placement is another important milestone in AD progression. The desire and decision to
place patients with AD in full-time nursing care varies
with each patient (based on severity of disease and neuropsychiatric symptoms) and the caregiver’s circumstances, including financial resources and caregiver
ability. In general, families probably prefer to keep the
patient at home as long as possible. Conversely, some
caregivers would prefer to place a patient under fulltime professional care, but cannot afford to do so. If the
patient is a widow/er and the adult children live far
away, the preference may be for earlier placement
because geographic constraints prohibit at-home care.
Studies of cholinesterase inhibitors’ effect on nursing
home placement have yielded mixed results, possibly
because of these varying influential factors.
One study of donepezil versus placebo estimated
(conservatively) that proper use of donepezil over 9 to
12 months (ie, therapeutic doses and high compliance
rates) resulted in a delay of nursing home placement of
21.4 months for a first-time dementia-related placement and 17.5 months for permanent placement.70
The authors note that “doctors and caregivers need to
be educated that, in the same way as the actual benefits of treating hypertension or hyperlipidemia are seen
only after years of treatment, treatment of AD with
donepezil needs to be maintained to see important
long-term benefits.”70 A study in the United Kingdom
of donepezil showed no difference in institutionalization after 3 years of follow-up, but the decision to
place patients in nursing homes or even to treat with a
cholinesterase inhibitor was based on different factors
from those in the US healthcare system.71 In clinical
practice, a typical drug trial for a cholinesterase
inhibitor would be approximately 4 months (for titration up to the therapeutic and best-tolerated dose) to
see some stabilization in memory, function, and/or
Advanced Studies in Nursing
n
behavior. If no change is observed, a different drug in
this class can be tried.
Head-to-head comparisons
Direct comparisons of cholinesterase inhibitors are
rare in the published literature. A comparison of galantamine to donepezil revealed no significant differences
between the 2 treatment groups at study end (52
weeks) in measures of ADLs and neuropsychiatric
symptoms.72 However, cognition measures showed a
greater benefit with galantamine treatment, maintaining baseline levels with galantamine but worsening
with donepezil.72
Cholinesterase inhibitors and anticholinergic drugs
Anticholinergic drugs are part of many therapeutic
drug classes and are commonly prescribed. They are
notorious for producing undesirable cognitive effects,
to which patients with AD are especially sensitive.
Their concurrent use is likely to negate any of the cognitive benefit with cholinesterase inhibition. A crosssectional study of Iowa Medicaid beneficiaries aged 50
years and older indicated that a surprising 35.4% of
these patients received concurrent anticholinergic
agents with cholinesterase inhibitors. Roughly 33% of
patients received an anticholinergic agent within 90
days (before or after) of starting the cholinesterase
inhibitor.73 Nurses should evaluate their patients’ drug
profiles at each visit, especially when a cholinesterase
inhibitor is prescribed, to avoid this unfortunate situation. Negating the effects of cholinesterase inhibitors
incurs significant burden and cost to the patient and
the healthcare industry.
NMDA ANTAGONISTS
Memantine is the only NMDA antagonist
approved for the treatment of AD. Its efficacy was
demonstrated in 2 randomized, double-blind, placebo-controlled studies in the United States.74,75 In addition to those studies, memantine was compared to
placebo in patients already receiving stable doses of
donepezil and showed an added benefit when coadministered with this cholinesterase inhibitor, with
regard to measures of cognition, ADLs, global outcome, and behavior.75 An oral solution of memantine
was recently approved by the FDA, which offers an
alternative that may make administration easier for
patients who have trouble swallowing tablets or prefer
taking medication in liquid form.
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REVIEW
In all of the studies of AD drugs, it is important to
remember that the results are a summation of effect on
the entire study group. Individual patients respond to a
drug to varying degrees, with some patients improving
markedly and others showing mild or even no improvement. The only way to know whether a particular patient
will respond to any of these drugs is to try. A drug trial is
worth the cost because the loss in ADLs and memory and
effects on behavior as a result of AD are devastating.
VITAMINS E AND C
Vitamin E is found in all cell membranes and helps
to maintain cell membrane structure. Vitamin E also
acts as an antioxidant by neutralizing the effects of
oxygen free radicals. Vitamin E is able to donate a
hydrogen atom, thus stabilizing the reactive species
with the unpaired electron. Vitamin C may be
involved in “recycling” the vitamin E from its oxidized
form for further use and is also a known antioxidant.76
The recommended daily allowance of vitamin E is
22 IU for adults, which can typically be obtained
through the diet.76 As recently reviewed, the few studies
evaluating vitamin E and/or C for prevention of AD
(through diet or nutritional supplements) do not provide any clear direction, although there is a lot of interest in their use. Some studies show a benefit with 1 or
both vitamins, whereas other studies show no effect.76,77
In a recent study in patients with MCI, the effects of
2000 IU vitamin E, 10 mg donepezil, and placebo were
compared over 3 years of treatment. There was no significant difference in the rate of progression to AD
among the 3 groups, although donepezil showed some
benefit during the first 12 months and in apolipoprotein E (APOE)-«4 allele carriers.78
It is difficult to identify the most appropriate role
of vitamin E for AD. Variations in study design and
source of the vitamins (diet, daily supplement, and
multivitamin) make an overall interpretation of vitamin E/C efficacy difficult.76,77 Another confounding
factor is whether the role of vitamins E and/or C
should be used as treatment with AD diagnosis or as a
preventive measure. The recent meta-analysis regarding high-dose vitamin E supplementation and risk of
all-cause mortality and the strong response from the
medical community underscore the ambiguous role of
vitamin E for chronic diseases. The study raised several issues regarding vitamin E that need to be investigated.79,80 Nonetheless, leading medical organizations
(as discussed later in this article) endorse consideration
266
of vitamin E for treatment of AD at a recommended
dose of 2000 IU, except in patients with vitamin K
deficiency (in whom this large dose may exacerbate
coagulation defects).
ANTI-INFLAMMATORY AGENTS
Over the past 5 to 10 years, several studies have suggested that anti-inflammatory drugs (nonsteroidal antiinflammatory drugs [NSAIDs]) are associated with a
decreased incidence of AD. A 2003 meta-analysis of the
existing literature (using 9 studies) showed that the relative risk of AD among users of NSAIDs was 28%
lower than among nonusers of NSAIDs.81 Among
short-term users (ie, <1 month), the risk was 5% lower,
increasing to 17% reduced risk among intermediate
users (<24 months) and further still to 73% lower risk
among long-term users (mostly >24 months).
Therefore, the benefits with NSAID use may increase
with longer use. In studies of aspirin as the only
NSAID, the relative risk of AD was reduced 13%.81
A 2004 meta-analysis of 11 studies assessing the
benefits of exposure to nonaspirin NSAIDs showed
that the risk for development of AD was cut 50% with
NSAID exposure.82 Among the prospective studies,
the risk was reduced 26% for lifetime NSAID exposure and 58% for use of at least 2 years.82 Therefore,
NSAID use may have a preventive benefit, but the
appropriate timing of exposure remains to be studied.
Studies of prednisone and a comparison of rofecoxib (a COX-2 inhibitor) and naproxen (an NSAID)
showed no benefit in cognition measures in patients
with AD.83,84 The benefits of NSAIDs vary and do not
seem to extend after the onset of dementia. Therefore,
NSAIDs are currently not considered to be an appropriate treatment for dementia.
STATINS
Cholesterol is synthesized only in the liver and brain.
One of the enzymes involved in cholesterol synthesis is
inhibited by the class of drugs used to treat dyslipidemia—statins. In the brain, cholesterol is synthesized
primarily in astrocytes and is transported elsewhere
through apolipoproteins, including APOE (a gene in
which a type 4 allele is a risk factor for AD). The exact
relationship between cholesterol levels and AD risk or
progression is unclear. Serum cholesterol levels do not
appear to correlate with risk of AD, and statin levels do
not affect production of β amyloid in humans, although
they do have an effect in vitro and in mice.85 However,
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some recent case-control studies suggest decreased risk of
AD with statins, but this is not fully supported by
prospective studies.86-88 Statins may offer a neuroprotective or anti-inflammatory effect, rather than prevent
accumulation of β-amyloid plaques.85
There are limited clinical studies of statins for AD.
Atorvastatin showed some clinical benefit in cognition
after 1 year of treatment (compared to placebo), but
the difference was not statistically significant.89 It
should be noted that this was a pilot study; the final
participant numbers at 12 months were low (n = 46).89
Another study of simvastatin (6 months) showed significant reductions in cerebrospinal fluid levels of
some but not all AD-related proteins (eg, tau, phosphorylated tau, β amyloid, and other proteins) and
slight improvement in cognition.90 Clearly, more studies are needed, but thus far data do not support a role
for statins in the treatment of AD.
THERAPEUTIC CHOICES
The American Psychiatric Association and the
American Academy of Neurology (AAN) have published
consensus guidelines on the treatment of patients with
dementia.91-93 The American Geriatrics Society has
endorsed the AAN guidelines, and guidelines for family
physicians have also been published.94,95 All of these professional organizations recommend the use of acetylcholinesterase inhibitors for treatment of mild to
moderate AD, noting comparable efficacy among the 3
drugs and the importance of clearly conveying expected
outcomes to patients and family members/caregivers. All
3 guidelines recommend vitamin E or support consideration of its use to slow or delay disease progression, but
they cite insufficient evidence to support the use of antiinflammatory medications in patients with AD.91-93,95
However, these guidelines were established before many
of the NSAID or statin study publications. In fact,
statins and memantine are not mentioned in any of the
current guidelines.
CONCLUSIONS
The emerging details of AD pathophysiology provide possible therapeutic targets. β-amyloid plaques
and NFTs are the long-held hallmarks of AD, but it
appears that they (along with the reduced neuronal
function and neurotransmitter availability) occur years
before clinical symptoms emerge. Future treatment
strategies will probably focus on the pathophysiologic
changes in AD and address multiple mechanisms. In
Advanced Studies in Nursing
n
the meantime, we have 4 drugs with proven efficacy,
albeit modest, in at least some patients with AD.
Although some may argue, based on clinical studies,
that the effect of cholinesterase inhibitors or memantine is minimal, in reality any preservation of function
and delay of nursing home placement in an individual
patient has important and permanent consequences.
The primary care nurse, in identifying and managing
a patient with AD, needs to understand each of the
following aspects of AD treatment: the expected outcomes with these drugs and their impact on the
patient and caregiver, the importance of reiterating
these expectations to the patient and caregiver, the
common concurrent prescribing of cholinesterase
inhibitors with anticholinergic drugs in older adults,
the use of newer agents as possible preventive treatments for AD, and any updates in recommended treatment strategies from leading medical organizations.
Because of the profound and sometimes rapid loss of
memory and function with AD, the importance of trying at least 1 of these treatments in a patient with AD
cannot be overstated.
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