THE PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE …€¦ · 256 Vol. 3, No. 8 October 2005 ABSTRACT...

256 Vol. 3, No. 8 n October 2005

ABSTRACT

The pathophysiology of Alzheimer’s disease(AD) is complex, involving several neurotransmit-ter systems and pathophysiologic processes. The 3hallmarks of AD—β-amyloid plaques, neurofibril-lary tangles, and neuronal cell death—are wellknown and central factors in AD pathology. Thesehallmarks, combined with our information on neu-rotransmitter involvement, are specific to ADbased on the timing, sequence, and location ofthese changes. This article reviews the pathophys-iology and course of brain damage seen duringAD progression, from preclinical to severe stages.Understanding these processes is fundamental inunderstanding AD progression and symptommanifestation, and in assessing the potential risksand benefits of therapeutic interventions. Thereare now 5 approved drugs for the cognitive symp-toms of AD—4 acetylcholinesterase inhibitors(approved for mild to moderate AD) and 1 non-competitive glutamate receptor antagonist(approved for moderate to severe AD). Recentstudies with these drugs are focusing on longer-term follow-up (1 year and beyond), in addition tomore “clinically relevant” outcomes, such as measures of function and nursing home

placement. Other treatments (vitamins E and/orC, nonsteroidal anti-inflammatory drugs, andstatins [cholesterol-lowering drugs]) show somepromise in preventing or delaying AD progres-sion, although more data are needed. There arenow several published guidelines for the treat-ment of AD. Although some may argue that theeffect of these drugs is modest, any preservationof function and delay of nursing home placementhas important and permanent consequences forthe patient and caregiver. The profound andsometimes rapid loss of memory and functionwith AD underscores the importance of trying atleast 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 charac-terized on a macro level as the progressive loss of braintissue. As the disease progresses, neurons die in a par-ticular pattern over time. One of the earliest signs ofAD is memory loss, particularly short-term recall. Thebrain areas involved in memory include the cortex,especially the hippocampus (Figure 1).1 Preclinical ADbegins in the entorhinal cortex, which connects thehippocampus, the structure responsible for memoryformation (short- and long-term memory; Figure 2),to the cerebral cortex.1 Several studies, such as onesincluding magnetic resonance imaging, suggest thatneuronal loss (measured by atrophy in select regions)may start years before signs of memory loss emerge.2,3

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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†

*Clinical Nurse Specialist Coordinator, Department ofPsychiatry, Alzheimer’s Disease Research Center, The JohnsHopkins Hospital, Baltimore, Maryland.

†Professor of Psychiatry and Behavioral Sciences,Codirector, Division of Geriatric Psychiatry andNeuropsychiatry, The Johns Hopkins Hospital, Baltimore,Maryland.

Address correspondence to: Ann S. Morrison, PhD, RN,CS, Clinical Nurse Specialist Coordinator, Department ofPsychiatry, Alzheimer’s Disease Research Center, The JohnsHopkins Hospital, 550 Broadway Avenue, Baltimore, MD21205. E-mail: [email protected].

Advanced Studies in Nursing n 257

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As the brain atrophies, cerebrospinal fluid fills in thespace previously occupied by brain tissue.

In mild to moderate AD, patients experience moreprominent memory loss (eg, difficulty recalling well-known names and confusion about familiar places), adecline in the ability to process complex thoughts (eg,difficulty with balancing the checkbook or preparing ameal), and mood and personality changes. In thebrain, atrophy extends to other areas of the cerebralcortex (Figure 3).1

At the later stages of AD progression, the cortex hasatrophied in areas that control speech, reasoning, senso-ry processing, and conscious thought (Figure 4).1,4 Asexpected with this degree of brain atrophy, the symp-toms of severe AD increase in severity (ie, impaired long-term memory, seizures, incontinence, weight loss, norecognition of loved ones, inability to sit up, and groan-ing/moaning/grunting). The progression of atrophythroughout the brain is diagrammed in Figure 5.1

DEGENERATIVE PROCESSES IN ALZHEIMER’S DISEASE

On a micro level, AD is characterized by 3 neu-ropathologic hallmarks: extracellular plaques of β-amy-loid protein (amyloid plaques), intracellularneurofibrillary tangles (NFTs), and neuronal degenera-tion. Plaques and NFTs were first discovered by AloisAlzheimer in a 1906 autopsy of a demented patient.Although they are a defining component of AD, theyare not unique to AD. Plaques and NFTs occur withnormal aging and in some other neurodegenerative dis-orders. In AD, plaques and NFTs are localized to areasin the brain that correspond to clinical symptoms.

Figure 1. Major Areas of the Brain

Copyright ©2002, Christy Krames.

HippocampusBrain Stem

Cerebellum

Thalamus

Cerebral CortexCorpus Callosum

Side view of the brain

Hypothalamus

Figure 2. Brain Changes in Preclinical Alzheimer’sDisease

Reprinted with permission from Alzheimer’s Disease Education and ReferralCenter Web site. Available at: http://www.alzheimers.org/unraveling/04.htm.Accessed June 17, 2005.1

CerebralCortex

EntorhinalCortex

Hippocampus

Figure 3. Brain Changes in Mild to ModerateAlzheimer’s Disease


ModeratelyEnlargedVentricles

Shrinkage ofHippocampus

CorticalShrinkage

Figure 4. Brain Changes in Severe Alzheimer’sDisease


Extreme Shrinkage ofCerebral Cortex Severely

EnlargedVentricles

ExtremeShrinkage ofHippocampus


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β-amyloid plaques are thought to play the centralrole in AD pathogenesis (the “amyloid hypothesis”),with several diverse pathophysiologic processes thatfollow (Figure 6), described as an “amyloid cascade.”5

The AD pathophysiologic cascade is complicated, buteach discovery of a neurotransmitter or pathologicprocess leads to the potential discovery of new thera-peutic targets.

The β-amyloid hypothesisβ-amyloid plaques are clumps of insoluble peptides

that result from the abnormal cleavage of amyloid pre-cursor protein (APP), the exact function of which isunknown. APP is normally cleaved by 3 enzymes—β-secretase, γ-secretase, and α-secretase. Cleavage by β-secretase, followed by γ-secretase, yields a soluble 40amino acid peptide (Figure 7).1 In AD, a variant formof 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 identifiableclumps termed β-amyloid plaques (Figure 8).1 α-secre-tase actually serves a protective function as it cleavesAPP at a site that prevents Aβ formation.

Genetic studies of AD support the role of γ-amy-loid 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 beinvolved with the formation of Aβ. (The use of italicsindicates a gene, whereas normal font indicates theprotein made from the gene.) APP is the gene thatcodes for APP (the protein) and is located on chromo-some 21. Interestingly, people with Down’s syndrome(trisomy 21—3 copies of chromosome 21) ultimately

develop AD at a younger age than the general popula-tion.6 PS1 and PS2 are genes that code for presenilin,the catalytic subunit of γ-secretase. There are at least20 known mutations of APP, more than 140 knownmutations in PS1, and approximately 10 in PS2.6,7

Immunization against Aβ is under investigation as atreatment in animals and humans.8-11

Neurofibrillary tangles are seen as dying or deadneurons when viewed after histologic staining. NFTsresult from the destruction of neuronal microtubulescaused by the modification of their supporting pro-tein, tau (Figure 9).1 Microtubules are essential com-ponents of neuronal cell structure; they act as tracksalong which nutrients are delivered and neuronaltransmission is propagated in the neuronal axon.During AD pathogenesis, tau proteins become hyper-phosphorylated, disrupting their bonds to micro-tubules, thus collapsing microtubule structure and

Figure 5. Brain Damage and Atrophy During Alzheimer’sDisease Progression

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 CenterWeb site. Available at: http://www.alzheimers.org/unraveling/04.htm. Accessed June17, 2005.1

A B C

Figure 6. Diagram of the Amyloid Cascade

APP = amyloid precursor protein.Reprinted with permission from Cummings. N Engl J Med. 2004;351:56-67.5

Cytoplasm

Cellmembrane

Extracellularspace

p3APP

α-APPβ-APP

Aββ-secretase

γ-secretaseγ-secretase

α-secretase

Aβ generation

Oxidation Excitotoxicity Aβ aggregation Inflammation Tau hyperphosphorylation

Cognitive and behavioralabnormalities

Neuro-transmitter

deficit

Celldeath

Neuron

Senile plaque with microglial activation

Neurofibrillarytangles


destroying the neuron’s transport and communicationsystem. Neuronal cell death ensues. Although thecausal relationship is unclear, hyperphosphorylation oftau is thought to occur after plaque formation.12,13

The cholinergic hypothesisLoss of cholinergic neurons is another well-estab-

lished pathology of AD. By late-stage AD, the numberof cholinergic neurons is dramatically reduced; insome parts of the brain there is more than 75% loss.14

Acetylcholine is an important neurotransmitter inbrain regions involving memory, and loss of choliner-gic activity correlates with some aspects of cognitiveimpairment. Cholinergic abnormalities are the mostprominent neurotransmitter changes in AD.

Acetylcholine binds to 2 postsynaptic receptortypes: muscarinic and nicotinic. Presynaptic nicotinicreceptors influence the release of neurotransmittersimportant for memory and mood—acetylcholine, glu-tamate, serotonin, and norepinephrine—all of whichhave been implicated in AD pathology.

The glutamatergic/excitotoxicity hypothesisGlutamate is the primary excitatory neurotrans-

mitter in the brain. In the central nervous system, it isvirtually ubiquitous and is estimated to be involved inroughly 66% of all brain synapses.15,16 Glutamatergicneurons are also critical because they form projectionsto other areas of the brain, including cholinergic neu-rons, thus influencing cognition. In AD, the patholo-gy associated with glutamatergic neurons is not withglutamate itself but with the levels of pre- and postsy-naptic glutamate receptors. Of the 3 types of postsy-naptic glutamate receptors, AD pathology has onlybeen linked to 1 type, the N-methyl-D-aspartate(NMDA) receptor, which appears to undergo sus-tained low-level activation in AD brains, causing sus-tained low-level neurotransmission. This dysregulationat the glutamate NMDA receptor is thought to per-petuate a vicious cycle of neuronal damage, in whichcontinuous activation of the receptor leads to chroniccalcium influx within the neuron that interferes withnormal signal transduction.17 It also leads to increasedproduction of APP, which, as noted earlier in this arti-cle, is associated with higher rates of plaque develop-ment and hyperphosphorylation of tau protein (thusNFT formation) followed by neuronal toxicity.18-21

Glutamate is cleared from the synapse by reuptake intothe nerve terminal and surrounding glial cells.

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Figure 7. The Structure of Amyloid PrecursorProtein Relative to the Cell Membrane

Amyloid precursor protein is a transmembrane protein. Cleavage by β-sec-retase, followed by γ-secretase, yields a soluble 40 amino acid peptide. Thispeptide is shown here in green.Copyright ©2002, Christy Krames.

β-amyloid

Enzymes

Figure 8. Insoluble Aggregates of Aβ42


Figure 9. The Role of Tau Protein in Neuronal CellDeath


β-amyloidPlaque

StabilizingTau Molecules

Healthy Neuron

Microtubules

Diseased Neuron

DisintegratingMicrotubule

DisintegratingMicrotubules

Microtubule SubunitsFall Apart

Tangled Clumpsof Tau Proteins


Dementia patients also appear to have reduced num-bers of glutamate reuptake sites or abnormal expres-sion of a glutamate transporter, which may be linkedto NFT formation.22,23

The oxidative stress hypothesis In AD brains, Aβ induces lipid peroxidation and

generates reactive oxygen and nitrogen species; theseare oxygen or nitrogen molecules containing anunpaired extra electron (termed species) that reactswith other molecules to achieve a stable configuration.During this process, the reactive species forms a mole-cular bond with another molecule, while a high-ener-gy electron (termed a “free radical”) is thrown off. Thereaction is permanent, thus structurally and function-ally altering the molecule to which the reactive speciesis attached. The free radical is left to cause cellular andmolecular damage. This oxidative damage can occur invirtually all types of neuronal macromolecules (eg,lipids, carbohydrates, proteins, and nucleic acids). Thebrain is especially vulnerable to damage from oxidativestress because of its high oxygen consumption rate,abundant lipid content, and relative paucity of antiox-idant enzymes compared to other organs. In neurons,oxidation can result in numerous problems, includingupregulation of proinflammatory cytokines andirreparable DNA damage.24,25 Oxidative stress isthought to be important early in AD progressionbecause it is temporally linked to the development ofplaques and NFTs.26

The chronic inflammation hypothesisβ-amyloid deposits, NFTs, and damaged neurons

may stimulate inflammation as a natural response tocell damage. Microglia (1 of 4 types of brain cells,including neurons, astrocytes, and oligodendrocytes)are involved in immune and inflammatory responsesto injury or infection within the brain. During ADpathogenesis, microglia are activated to release poten-tially cytotoxic molecules, such as proinflammatorycytokines, reactive oxygen species, proteinases, andcomplement proteins.27 This is a normal response tocellular damage that, in AD, appears to proceed unin-hibited, causing more harm than protection. Cytokinesstimulate inflammatory processes that may promoteapoptosis (programmed cell death) of neurons and oligo-dendrocytes and induce myelin damage. Inflammationas part of AD pathology has been observed as increasedprostaglandins, which are produced by the cyclooxyge-

nases COX-1 and COX-2, in the AD brain.28 It is inter-esting to note that the inflammation in AD is chronicand localized to discrete areas of the brain, as are theother types of cellular damage with AD.29

Other neurotransmitter deficienciesDuring the AD process, brain regions in which

acetylcholine, serotonin, and norepinephrine areprominent become altered, affecting widespreadareas of the cerebral cortex. Serotonin is known to beimportant in affective illness (eg, depression and anx-iety), and depression is a common comorbidity withAD. The number of serotonin receptors and trans-porters are altered in AD brains, corresponding todecline in measures of cognition and presence of anx-iety.30-32 Also, norepinephrine levels are reduced andnorepinephrine neurons are lost in AD.33

Norepinephrine may play an important role in someof the behavioral and psychological symptoms ofdementia (aggression, agitation, and psychosis), inaddition to memory loss.34

CholesterolCholesterol is also now thought to be involved in

AD pathogenesis. The brain contains the highestamount of cholesterol of any human organ.35

Elevated cholesterol levels appear to increase Aβ pro-duction, whereas reduced cholesterol synthesis (eg, asa result of statin drugs) reduces Aβ levels, thus therisk of AD progression.36 Cholesterol reduction mayalso reduce the risk or severity of dementia throughprotection from vascular risk factors; vascular demen-tia often coexists in patients with AD. In theHonolulu-Asia Aging Study, cholesterol levels of 218Japanese-American men were measured at mid-lifeand late-life. At autopsy, there was a strong linearassociation between mid-life and late-life high-densi-ty lipoprotein cholesterol and the number of plaquesand NFTs in the cortex.37

SUMMARY

Our understanding of AD pathology is nowextending beyond the details of pathophysiologicprocesses to a broader view of the sequence and tim-ing of these events in the development of symptomsand illness progression. Aβ generation is consideredto be the first step of an “amyloid cascade,” whichcontinues with oxidation, excitotoxicity, inflamma-tion, and the hyperphosphorylation of tau. Each of

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these processes contributes to neurotransmitterabnormalities and neuronal cell death, which thenmanifest as cognitive and behavioral abnormalities.5

KEY POINTS

• In AD, brain atrophy and neuronal loss occur ina predictable pattern beginning with the entorhi-nal cortex and hippocampus, ultimately progress-ing throughout the brain.

• AD is characterized by 3 neuropathologic hall-marks: plaques of β-amyloid protein (amyloidplaques), NFTs, and neuronal degeneration, allof which occur during normal aging, but in ADoccur in specific locations in the brain.

• β-amyloid plaques are thought to play the centralrole in AD pathogenesis, described as the “amy-loid cascade.”

• The β-amyloid hypothesis maintains that forma-tion of β-amyloid plaques is the first step in ADpathology, and genetic and histopathologic stud-ies support this hypothesis. NFTs occur afterplaque formation.

• The cholinergic hypothesis is supported by thedrastic and widespread loss of cholinergic neu-rons in AD, the benefits with acetylcholinesteraseinhibitors, and the role of the nicotinic choliner-gic receptor.

• The glutamate/excitotoxicity hypothesis main-tains that slow but steady activation of a gluta-mate receptor leads to cellular damage.

• The oxidative stress hypothesis suggests that β-amyloid induces oxidative stress causing perma-nent damage to some neuronal macromolecules(especially lipids) and creating reactive species,which further propagate neuronal toxicity.

• The chronic inflammation observed with AD isthought to be the result of all of these mecha-nisms causing cell damage and death. In AD,inflammatory cytokines respond to these process-es and contribute to neuronal destructionbecause they appear to act uninhibited.

• Serotonin and norepinephrine are also involvedin AD pathology. Serotonin is an important fac-tor in depression and anxiety, both of which arecommon in patients with AD.

• Cholesterol also appears to have a role in ADprogression, perhaps through a reduction in vas-cular risk factors, which are common in patientswith AD.

TREATMENTS FOR ALZHEIMER’S DISEASE

OVERVIEW

Pharmacologic treatments for the primary symp-toms of AD, namely memory loss and cognitiveimpairment, have only become available within thepast decade. Four of 5 approved therapies (tacrine,donepezil, rivastigmine, and galantamine) act byinhibiting the enzyme acetylcholinesterase, which isresponsible for breaking down acetylcholine postsy-naptically, thus keeping acetylcholine in the synapselonger. As described earlier in this article, cholinergicneuron loss is the primary type of neurodegenerationin AD. The fifth drug, memantine, acts as a noncom-petitive antagonist to the NMDA receptor, curtailingthe low-level but steady NMDA receptor activationthought to occur in AD and contributing to excito-toxicity.17 Several other treatments that address notonly the symptoms but also the pathophysiologicprocesses in AD are also under investigation.

CHOLINESTERASE INHIBITORS

Although there are 4 approved cholinesteraseinhibitors, only 3 are commonly used in the UnitedStates. The fourth, tacrine, is still available but rarelyprescribed because of the potential hepatotoxicityassociated with its use; it also has a complicated titra-tion schedule. Tacrine should probably never be rec-ommended as first-line therapy for AD. Although it isstill on the market, there is no practical use for tacrinein the treatment of AD. However, nurses may stillencounter prescriptions for it. A summary of the rec-ommended dosing and titration schedule, in additionto common adverse events with each drug, are listed inTable 1.38-41 Donepezil, rivastigmine, and galantamineare indicated for mild to moderate AD; memantine isindicated for moderate to severe AD.

Donepezil was the first drug to be approved by theUS Food and Drug Administration (FDA) for thesymptoms of mild to moderate AD. Its efficacy wasestablished in 2 randomized, double-blind, placebo-controlled studies.42,43 Donepezil was followed byrivastigmine, the clinical efficacy of which was shownin 3 randomized, placebo-controlled studies in theUnited States and internationally.44-46 The efficacy ofgalantamine was demonstrated in 4 randomized, dou-ble-blind, placebo-controlled studies—2 in the UnitedStates and 2 in other countries.47-50 The initial safetyand efficacy studies were typically shorter than 6


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months. Current studies of AD drugs are focusing onlonger follow-up, other AD-related indications (eg,mild cognitive impairment [MCI] and more severestages of AD), nursing home placement, vascular riskfactors, and the pathophysiology of AD.

Long-term follow-upThere has been 1 long-term study of donepezil that

extended to 4.9 years, an extension of an original 14-week study.42 The results showed evidence of clinicalbenefit (ie, maintenance of baseline scores for cogni-tion measures) during the first 6 to 9 months of open-label treatment, with gradual cognitive decline after 9months. The treatment group was compared to histor-ical controls, which was a serious methodologicalproblem for this study. The rate of cognitive declinethroughout the nearly 5-year study was slower forthose patients receiving donepezil than the estimatesfor patients who had not been treated.51 The benefitswith rivastigmine have been shown in studies of 1- and2-years’ duration. In the 1-year studies, differences incognitive decline as measured by the AD assessmentscale-cognitive subscale were -4.45 ± 0.8 (placebo) ver-

sus 0.82 ± 0.71 (rivastigmine) and -8.0 (historical place-bo) versus -3.8 (rivastigmine).52,53 In the 2-year study, cog-nitive decline slowed by 35% in those patients receivingrivastigmine compared to a historical placebo group.54

Improvement with rivastigmine was also observed in asubgroup of moderately severe patients.55 The long-termefficacy of galantamine was shown in 3 studies. In an18.5-month study, patients taking galantamine enjoyedsustained cognitive benefits during the entire study dura-tion.56 In two 3-year studies, galantamine was associatedwith a roughly 50% slower cognitive decline compared topredicted rates of decline in a clinically similar historicalcontrol sample of patients with AD.57,58

Disease severityDonepezil has shown significant benefit on mea-

sures of cognition compared to placebo in patientswith “early stage” (mild) AD.59 An important observa-tion in this study population is that the placebo groupshowed virtually no signs of cognitive decline (as mea-sured by the Mini-Mental State Examination[MMSE]) during the study period, whereas in studiesof patients with mild to moderate AD, patients receiv-

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Table 1. The Currently Available Treatments for AD Symptoms—A Summary*

Drug AD Indication Dosing Common Adverse Events†

Donepezil Mild to moderate 5 mg or 10 mg; treatment with a 10-mg dose Nausea, diarrhea, insomnia, vomiting, muscleshould not be considered until patients have been cramps, fatigue, and anorexiaon a daily dose of 5 mg for 4 to 6 weeks to avoid adverse events

Rivastigmine Mild to moderate 3–6 mg twice daily; starting dose: 1.5 mg twice daily; Nausea, vomiting, loss of appetite, dyspepsia,increase to 3 mg twice daily after 2 weeks; other asthenia, and weight lossdose increases should be separated by at least 2 weeks

Galantamine Mild to moderate 8–12 mg twice daily, preferably with morning and Nausea and vomitingevening 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 constipationtitration: increase in 5-mg increments to 10 mg/d (5 mgtwice 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

ing placebo showed cognitive decline in MMSE scoresduring the study.59 Therefore, the extent of observeddonepezil benefit may depend on the level of ADseverity. At the other end of the severity spectrum,donepezil was compared to placebo in patients withmoderate to severe AD and showed significant benefitin cognition measures at all time points during the 6-month study.60

Two studies have analyzed the effect of rivastigminebased on disease severity, but from a different approach.In a 1-year study, patients were classified as slowly pro-gressive or rapidly progressive, based on the magnitudeof response seen in the first 6 months of the study. Thefinal results showed notable and significant differences inresponse to rivastigmine between these 2 groups ofpatients, with patients who were rapidly progressiveobtaining greater benefit from rivastigmine treatment.61

In a 12-month study of patients with mild AD or MCI,cognitive function was slightly improved or maintainedin the patients with mild AD and unchanged or slightlyworsened in the patients with MCI (both groups receiv-ing rivastigmine); cognitive function was markedly wors-ened in untreated patients with AD.62

Functional measuresResearchers are now turning to more “clinically rel-

evant” outcomes, such as functional decline (ie, abilityto perform activities of daily living [ADLs] or instru-mental ADLs [IADLs]), nursing home placement, andeffect on caregiver burden. ADLs focus on basic func-tioning, such as toileting, feeding, dressing, bathing,walking, and grooming. IADLs are more complexactivities, which most adults of normal mental capaci-ty can perform, such as operating household appli-ances, paying bills and managing money, shopping,preparing meals, and participation in hobbies. Theeffect on ADLs is important for several reasons. ADLsinstill and maintain a sense of independence and self-efficiency, which is critical for patients’ and caregivers’quality of life. In AD, loss of ADLs is enduring and isa significant predictor of institutionalization.63

Therefore, preservation of ADLs is a critical outcomewith important and permanent ramifications.

A 1-year study of donepezil versus placebo suggest-ed that donepezil use may have effects on delaying lossof ADLs. Patients taking donepezil were 31% less like-ly to experience functional decline (ie, losing the abil-ity to perform an ADL or IADL) than those takingplacebo.64 The authors noted that patients on

donepezil tended to stabilize over time, rather than toimprove over baseline, “suggesting that cliniciansshould aim for stability rather than actual improve-ment in ADLs.”64 This is an important message to con-vey to patients and their caregivers as AD progressesand they consider treatment with a cholinesteraseinhibitor. Another study showed not only slowerdecline in ADLs and IADLs with donepezil treatmentbut also less decline in the components required forcompleting each ADL (initiation, planning and orga-nization, and effective performance).65 Caregiver bur-den was also measured as time required with thepatient for ADLs/IADLs and stress levels. Caregiversreported spending a mean of 52.4 fewer minutes/dayon ADLs and 17.2 fewer minutes/day on IADLs withdonepezil-treated patients. Almost all components ofthe caregiver stress scale favored donepezil. Theauthors also noted the importance of stabilizing cogni-tive function because the placebo group did not showa floor effect (ie, patients never reached a point atwhich further decline was not measurable).65

Rivastigmine has beneficial effects on ADLs, asshown 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 frombaseline based on 3 levels of severity.66

A secondary analysis of a 5-month study showed thatgalantamine treatment resulted in little or no declinefrom baseline in ADL measures compared to significantdecline in the placebo group.48,67 Galantamine treatmentresulted in maintenance or improvement in ADL andIADL measures, with significant improvement overplacebo in 3 of 6 basic ADLs (toileting, bathing, andgrooming) and 6 of 17 IADLs (conversation, managingpersonal belongings, current events, writing, hobbies,and operating household appliances).67 ADL stabiliza-tion was seen throughout the range of AD severity, butthe greatest differences were observed in those patientswith severe disease.67

Regarding caregiver time, galantamine also hasnotable effects. Pooled data from two 6-month studiesshow that caregivers reported spending a mean of 32fewer minutes per day with galantamine-treatedpatients than with placebo-treated patients, a savingsof approximately 3.5 hours per week. In patients withmoderate AD, the benefits were even greater—a meandaily time savings of 53 minutes or more than 6 hoursper week. Similarly, galantamine-treated patients couldspend 27 more minutes per day unsupervised and, in the


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moderate AD group, the benefit was extended to spend-ing 68 more minutes per day unsupervised.68

The profound consequences of maintaining ADLsis illustrated in a case study from Tariot and

Jakimovich, in which donepezil was administered to apatient with severe AD, behavioral problems, and sev-eral comorbidities following admission to a long-termcare facility.69 The positive effects of donepezil treat-

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Table 2. ADLs Affected Based on Degree of AD Severity with Rivastigmine or Placebo Treatment

GDS ≤3 GDS = 4 GDS ≥5

PDS Item Mean change Improvement, % Mean change Improvement, % Mean change Improvement, %

Cannot handle money -0.1 vs -4.1* 49 vs 33*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

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 -1.6 vs -6.9 45 vs 32

Drives car safely -1.9 vs -5.4 44 vs 33

Forgets things 0.9 vs -3.3* 52 vs 32* -1.5 vs -5.3* 40 vs 28*

Rearranges objects 0.7 vs -2.3 51 vs 38 -1.1 vs -5.8* 45 vs 30*Stops participation in family finances -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 measuredby 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

ment included engagement in meaningful conversa-tions about family events and current events seen ontelevision, although he was amnesic for details; coher-ent periods of (factually correct) reminiscence on hislife; and improved ability to perform ADLs, includingindependent toileting, reduced belligerent and sexual-ly inappropriate behavior, discontinuation of haloperi-dol, ability to travel to a family event, and restorationof walking ability; none of which were possible whenhe was admitted to the nursing facility.69

Nursing home placementNursing home placement is another important mile-

stone in AD progression. The desire and decision toplace patients with AD in full-time nursing care varieswith each patient (based on severity of disease and neu-ropsychiatric symptoms) and the caregiver’s circum-stances, including financial resources and caregiverability. In general, families probably prefer to keep thepatient at home as long as possible. Conversely, somecaregivers would prefer to place a patient under full-time professional care, but cannot afford to do so. If thepatient is a widow/er and the adult children live faraway, the preference may be for earlier placementbecause geographic constraints prohibit at-home care.Studies of cholinesterase inhibitors’ effect on nursinghome placement have yielded mixed results, possiblybecause of these varying influential factors.

One study of donepezil versus placebo estimated(conservatively) that proper use of donepezil over 9 to12 months (ie, therapeutic doses and high compliancerates) resulted in a delay of nursing home placement of21.4 months for a first-time dementia-related place-ment and 17.5 months for permanent placement.70

The authors note that “doctors and caregivers need tobe educated that, in the same way as the actual bene-fits of treating hypertension or hyperlipidemia are seenonly after years of treatment, treatment of AD withdonepezil needs to be maintained to see importantlong-term benefits.”70 A study in the United Kingdomof donepezil showed no difference in institutionaliza-tion after 3 years of follow-up, but the decision toplace patients in nursing homes or even to treat with acholinesterase inhibitor was based on different factorsfrom those in the US healthcare system.71 In clinicalpractice, a typical drug trial for a cholinesteraseinhibitor would be approximately 4 months (for titra-tion up to the therapeutic and best-tolerated dose) tosee some stabilization in memory, function, and/or

behavior. If no change is observed, a different drug inthis class can be tried.

Head-to-head comparisonsDirect comparisons of cholinesterase inhibitors are

rare in the published literature. A comparison of galan-tamine to donepezil revealed no significant differencesbetween the 2 treatment groups at study end (52weeks) in measures of ADLs and neuropsychiatricsymptoms.72 However, cognition measures showed agreater benefit with galantamine treatment, maintain-ing baseline levels with galantamine but worseningwith donepezil.72

Cholinesterase inhibitors and anticholinergic drugsAnticholinergic drugs are part of many therapeutic

drug classes and are commonly prescribed. They arenotorious for producing undesirable cognitive effects,to which patients with AD are especially sensitive.Their concurrent use is likely to negate any of the cog-nitive benefit with cholinesterase inhibition. A cross-sectional study of Iowa Medicaid beneficiaries aged 50years and older indicated that a surprising 35.4% ofthese patients received concurrent anticholinergicagents with cholinesterase inhibitors. Roughly 33% ofpatients received an anticholinergic agent within 90days (before or after) of starting the cholinesteraseinhibitor.73 Nurses should evaluate their patients’ drugprofiles at each visit, especially when a cholinesteraseinhibitor is prescribed, to avoid this unfortunate situ-ation. Negating the effects of cholinesterase inhibitorsincurs significant burden and cost to the patient andthe healthcare industry.

NMDA ANTAGONISTS

Memantine is the only NMDA antagonistapproved for the treatment of AD. Its efficacy wasdemonstrated in 2 randomized, double-blind, place-bo-controlled studies in the United States.74,75 In addi-tion to those studies, memantine was compared toplacebo in patients already receiving stable doses ofdonepezil and showed an added benefit when coad-ministered with this cholinesterase inhibitor, withregard to measures of cognition, ADLs, global out-come, and behavior.75 An oral solution of memantinewas recently approved by the FDA, which offers analternative that may make administration easier forpatients who have trouble swallowing tablets or prefertaking medication in liquid form.


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In all of the studies of AD drugs, it is important toremember that the results are a summation of effect onthe entire study group. Individual patients respond to adrug to varying degrees, with some patients improvingmarkedly and others showing mild or even no improve-ment. The only way to know whether a particular patientwill respond to any of these drugs is to try. A drug trial isworth the cost because the loss in ADLs and memory andeffects on behavior as a result of AD are devastating.

VITAMINS E AND CVitamin E is found in all cell membranes and helps

to maintain cell membrane structure. Vitamin E alsoacts as an antioxidant by neutralizing the effects ofoxygen free radicals. Vitamin E is able to donate ahydrogen atom, thus stabilizing the reactive specieswith the unpaired electron. Vitamin C may beinvolved in “recycling” the vitamin E from its oxidizedform for further use and is also a known antioxidant.76

The recommended daily allowance of vitamin E is22 IU for adults, which can typically be obtainedthrough the diet.76 As recently reviewed, the few studiesevaluating vitamin E and/or C for prevention of AD(through diet or nutritional supplements) do not pro-vide any clear direction, although there is a lot of inter-est in their use. Some studies show a benefit with 1 orboth vitamins, whereas other studies show no effect.76,77

In a recent study in patients with MCI, the effects of2000 IU vitamin E, 10 mg donepezil, and placebo werecompared over 3 years of treatment. There was no sig-nificant difference in the rate of progression to ADamong the 3 groups, although donepezil showed somebenefit during the first 12 months and in apolipopro-tein E (APOE)-«4 allele carriers.78

It is difficult to identify the most appropriate roleof vitamin E for AD. Variations in study design andsource of the vitamins (diet, daily supplement, andmultivitamin) make an overall interpretation of vita-min E/C efficacy difficult.76,77 Another confoundingfactor is whether the role of vitamins E and/or Cshould be used as treatment with AD diagnosis or as apreventive measure. The recent meta-analysis regard-ing high-dose vitamin E supplementation and risk ofall-cause mortality and the strong response from themedical community underscore the ambiguous role ofvitamin E for chronic diseases. The study raised sever-al issues regarding vitamin E that need to be investi-gated.79,80 Nonetheless, leading medical organizations(as discussed later in this article) endorse consideration

of vitamin E for treatment of AD at a recommendeddose of 2000 IU, except in patients with vitamin Kdeficiency (in whom this large dose may exacerbatecoagulation defects).

ANTI-INFLAMMATORY AGENTS

Over the past 5 to 10 years, several studies have sug-gested that anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs [NSAIDs]) are associated with adecreased incidence of AD. A 2003 meta-analysis of theexisting literature (using 9 studies) showed that the rel-ative risk of AD among users of NSAIDs was 28%lower than among nonusers of NSAIDs.81 Amongshort-term users (ie, <1 month), the risk was 5% lower,increasing to 17% reduced risk among intermediateusers (<24 months) and further still to 73% lower riskamong long-term users (mostly >24 months).Therefore, the benefits with NSAID use may increasewith longer use. In studies of aspirin as the onlyNSAID, the relative risk of AD was reduced 13%.81

A 2004 meta-analysis of 11 studies assessing thebenefits of exposure to nonaspirin NSAIDs showedthat the risk for development of AD was cut 50% withNSAID exposure.82 Among the prospective studies,the risk was reduced 26% for lifetime NSAID expo-sure and 58% for use of at least 2 years.82 Therefore,NSAID use may have a preventive benefit, but theappropriate timing of exposure remains to be studied.

Studies of prednisone and a comparison of rofe-coxib (a COX-2 inhibitor) and naproxen (an NSAID)showed no benefit in cognition measures in patientswith AD.83,84 The benefits of NSAIDs vary and do notseem to extend after the onset of dementia. Therefore,NSAIDs are currently not considered to be an appro-priate treatment for dementia.

STATINS

Cholesterol is synthesized only in the liver and brain.One of the enzymes involved in cholesterol synthesis isinhibited by the class of drugs used to treat dyslipi-demia—statins. In the brain, cholesterol is synthesizedprimarily in astrocytes and is transported elsewherethrough apolipoproteins, including APOE (a gene inwhich a type 4 allele is a risk factor for AD). The exactrelationship between cholesterol levels and AD risk orprogression is unclear. Serum cholesterol levels do notappear to correlate with risk of AD, and statin levels donot affect production of β amyloid in humans, althoughthey do have an effect in vitro and in mice.85 However,

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some recent case-control studies suggest decreased risk ofAD with statins, but this is not fully supported byprospective studies.86-88 Statins may offer a neuroprotec-tive or anti-inflammatory effect, rather than preventaccumulation of β-amyloid plaques.85

There are limited clinical studies of statins for AD.Atorvastatin showed some clinical benefit in cognitionafter 1 year of treatment (compared to placebo), butthe difference was not statistically significant.89 Itshould be noted that this was a pilot study; the finalparticipant numbers at 12 months were low (n = 46).89

Another study of simvastatin (6 months) showed sig-nificant reductions in cerebrospinal fluid levels ofsome but not all AD-related proteins (eg, tau, phos-phorylated tau, β amyloid, and other proteins) andslight improvement in cognition.90 Clearly, more stud-ies are needed, but thus far data do not support a rolefor statins in the treatment of AD.

THERAPEUTIC CHOICES

The American Psychiatric Association and theAmerican Academy of Neurology (AAN) have publishedconsensus guidelines on the treatment of patients withdementia.91-93 The American Geriatrics Society hasendorsed the AAN guidelines, and guidelines for familyphysicians have also been published.94,95 All of these pro-fessional organizations recommend the use of acetyl-cholinesterase inhibitors for treatment of mild tomoderate AD, noting comparable efficacy among the 3drugs and the importance of clearly conveying expectedoutcomes to patients and family members/caregivers. All3 guidelines recommend vitamin E or support consider-ation of its use to slow or delay disease progression, butthey cite insufficient evidence to support the use of anti-inflammatory medications in patients with AD.91-93,95

However, these guidelines were established before manyof the NSAID or statin study publications. In fact,statins and memantine are not mentioned in any of thecurrent guidelines.

CONCLUSIONS

The emerging details of AD pathophysiology pro-vide possible therapeutic targets. β-amyloid plaquesand NFTs are the long-held hallmarks of AD, but itappears that they (along with the reduced neuronalfunction and neurotransmitter availability) occur yearsbefore clinical symptoms emerge. Future treatmentstrategies will probably focus on the pathophysiologicchanges in AD and address multiple mechanisms. In

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 meman-tine is minimal, in reality any preservation of functionand delay of nursing home placement in an individualpatient has important and permanent consequences.The primary care nurse, in identifying and managinga patient with AD, needs to understand each of thefollowing aspects of AD treatment: the expected out-comes with these drugs and their impact on thepatient and caregiver, the importance of reiteratingthese expectations to the patient and caregiver, thecommon concurrent prescribing of cholinesteraseinhibitors with anticholinergic drugs in older adults,the use of newer agents as possible preventive treat-ments for AD, and any updates in recommended treat-ment strategies from leading medical organizations.Because of the profound and sometimes rapid loss ofmemory and function with AD, the importance of try-ing at least 1 of these treatments in a patient with ADcannot be overstated.

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