030911 early alzheimer's disease

The new england journal of medicine This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. A 72-year-old, college-educated woman comes in for the evaluation of mild memory
loss that has been gradually progressing for the past two years. The patient lives alone,
drives her own car, and manages her own finances, although she has recently made
some errors in her checkbook. She also forgot the location of her car in a mall parking
lot for two hours. Her score on the Mini–Mental State Examination is 26 of a possible
30, but she missed several items pertaining to memory. How should this patient be
evaluated and treated?
From the Institute for Brain Aging and De- At present, 4 million Americans have Alzheimer’s disease, and the number of cases is expected to quadruple by the middle of this century.1 Advancing age is the major risk gy and Neurobiology and Behavior, Univer- factor for dementia, with a doubling of risk every five years after the age of 65. Alzhei- sity of California, Irvine. Address reprintrequests to Dr. Kawas at the University of mer’s disease accounts for 50 to 75 percent of all cases of dementia. Other frequent California, Irvine, 1121 Gillespie, Irvine, CA causes of dementia include vascular dementia, either alone or in combination with Alz- heimer’s disease (in 10 to 20 percent of cases), dementia with Lewy bodies (in 10 to 15 percent), and frontotemporal dementia (in 5 to 15 percent). There are no definitive im- Copyright 2003 Massachusetts Medical Society. aging or laboratory tests for the diagnosis of dementia or most of the disorders thatcause dementia, including Alzheimer’s disease. The evaluation thus depends on carefulhistory taking in interviews with both the patient and a reliable informant, thoroughphysical and neurologic examinations (including careful testing of mental status), anduse of diagnostic criteria for dementia and Alzheimer’s disease that have high reliabil-ity and validity.
d e f i n i t i o n s o f d e m e n t i a , m i l d c o g n i t i v e i m p a i r m e n t , a n d n o r m a l a g i n g
The criteria for dementia as specified in the Diagnostic and Statistical Manual of Mental Dis-orders, third edition (revised)2 and fourth edition,3 require that a patient have cognitiveloss in two or more domains, such as memory, language, calculations, orientation, andjudgment. In addition, the loss must be of sufficient severity to cause social or occu-pational disability (Table 1). The use of neuropsychological tests and screening instru-ments, such as the Mini–Mental State Examination (MMSE)5 and the Blessed Infor-mation–Memory–Concentration test (IMC),6 is recommended to detect and followcognitive decline.7,8 The interpretation of scores depends on a person’s age and educa-tion level, but patients with cognitive losses in two or more domains typically have anMMSE score of less than 24 (the maximal score is 30 and the minimal score 0, with lowerscores indicating poorer performance) or an IMC score of more than 8 (the maximalscore [number of errors] is 33 and the minimal score 0, with higher scores indicatingpoorer performance).
Patients with profound memory loss without other cognitive impairments and pa- tients with minor impairments in numerous cognitive domains but no functional im- Downloaded from www.nejm.org on April 10, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2003 Massachusetts Medical Society. All rights reserved. pairment at work or home do not meet the criteriafor dementia. These patients are generally consid- Table 1. Criteria for the Diagnoses of Dementia, Probable Alzheimer’s Disease,
and Mild Cognitive Impairment.
ered to have mild cognitive impairment. These pa-tients’ MMSE scores are typically normal (24 to 28), Dementia*
but they often do poorly on the memory components Loss of memory and one or more other cognitive abilities (aphasia, apraxia, agnosia, or disturbance in executive functioning)† of the two tests (which require the recollection of Substantial impairment in social or occupational functioning (decline from a three words [on the MMSE] or the recollection of a name and address [on the IMC]). A more detailed Deficits that do not occur exclusively during the course of delirium evaluation of memory and cognition is generally Probable Alzheimer’s disease‡
necessary to confirm this diagnosis, and referral to a neuropsychologist is appropriate. When they are followed longitudinally, each year approximately 15 Cognitive loss documented by neuropsychological tests percent of patients with mild cognitive impairment No physical signs or neuroimaging or laboratory evidence of other diseases that could cause dementia (such as strokes, Parkinson’s disease, sub- have progression to dementia, usually Alzheimer’s Mild cognitive impairment§
Persons who are aging normally may also have Report (by the patient or an informant) of memory loss some mild deficits. For example, mental processing Abnormal memory performance for age (score >1.5 SD below mean for age) speed and memory for names decline with age, but Normal general cognitionNormal activities of daily living longitudinal investigations typically show the chang- es to be less than suggested by cross-sectional stud-ies.9,10 Moreover, these changes should not materi- * The criteria are consistent with those of the Diagnostic and Statistical Manual ally affect a person’s ability to function.
of Mental Disorders, third edition (revised) and fourth edition.2,3 † Apraxia refers to difficulty in sequencing voluntary motor movements (as in dressing), agnosia to difficulty in processing sensory input (as in recognizing s u b j e c t i v e s y m p t o m s r e l a t e d t o m e m o r y
objects by sight), and disturbance in executive functioning to difficulty in plan- With aging, people become increasingly likely to report subjective memory loss; the rate of such re- ‡ The criteria are consistent with the National Institute of Neurologic and Com- municative Disorders and Stroke–Alzheimer’s Disease and Related Disorders ports is 25 to 50 percent in community studies of Association (NINCDS–ADRDA) criteria.
persons over the age of 65. In most community stud- § The criteria are from Petersen et al.4ies, however, persons with subjective memory lossdo not have an increased risk of dementia unlessthey also have poor objective memory performance ning or magnetic resonance imaging (MRI) and(typically defined as a score more than 1.5 SD below blood assays (measurement of electrolyte levels, as-age- and education-specific norms on a memory sessment of hepatic, renal, and thyroid function,test).11,12 Highly educated people, however, may re- and measurement of the vitamin B level) should port subjective memory difficulties before cognitive be performed. Although hypothyroidism or vita-deficits can be demonstrated on tests commonly min B deficiency is rarely the cause of dementia, both are frequent coexisting conditions for whichtreatment is recommended.14,15 Screening for de-pression with the use of a brief instrument, such as s t r a t e g i e s a n d e v i d e n c e the Geriatric Depression Scale,16 is appropriate, but d i a g n o s i s
the clinician should also question the patient (sepa- The first issue is whether the patient has dementia rately from his or her family) and ask family mem-or mild cognitive impairment. If the history and re- bers about any depressive symptoms. Although de-sults of cognitive screening tests do not establish pression can mimic dementia, it occurs more oftenthe diagnosis, the patient should be referred for as a coexisting condition. Cognitive improvementmore extensive evaluation by a neuropsychologist.
after the treatment of depression does not rule out The routine workup for patients with demen- an underlying, early dementia.
tia or mild cognitive impairment should include In patients with dementia, the likelihood of Alz- careful history taking and physical and neurologic heimer’s disease is assessed largely on the basisexaminations, including tests of mental status. Med- of the history. According to the National Instituteications should be carefully reviewed. Non–con- of Neurologic and Communicative Disorders andtrast-enhanced computed tomographic (CT) scan- Stroke–Alzheimer’s Disease and Related Disor- Downloaded from www.nejm.org on April 10, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ders Association (NINCDS–ADRDA) criteria for routine clinical care of patients with suspected Alz-
probable Alzheimer’s disease,17 the cognitive loss heimer’s disease.
(in two or more domains, including memory) must
have an insidious onset and gradual progression. treatment of primary symptoms
In addition, other causes of dementia must be ruled Nonpharmacologic Management, Education,
out by examination, appropriate laboratory testing, and Support
and neuroimaging. Table 2 summarizes findings Since cognitive impairment is frequently exacer-
that may suggest a diagnosis other than Alzheimer’s bated by medications, medication use should be
disease, although sensitive and specific criteria for minimized, with particular attention to the use of
identifying these disorders in clinical practice are prescription sleeping pills, antianxiety medications,
not available.18-24
and over-the-counter preparations for sleep and Additional tests should be considered for pa- cold symptoms.
tients whose condition seems atypical. An electro- Safety issues, such as those related to driving, encephalogram is warranted if there is a history of should guide the clinician in determining when aseizures, loss of consciousness, episodic confusion, patient can no longer be left unsupervised. Patientsor rapid clinical decline. More extensive neuropsy- with mild Alzheimer’s disease will typically becomechological evaluation can facilitate diagnosis in pa- lost while driving before they have difficulty withtients whose symptoms are very mild or atypical or the process of driving itself. The first clinic visit iswhose history is unusual. A lumbar puncture should the time to begin working with the patient and fam-be performed in patients who have a history or signs ily to discontinue driving before serious safety risksof infection or cancer.
arise. Other signs that require immediate attention Apolipoprotein E genotyping and other genetic include the patient’s wandering or getting lost, leav- studies are not routinely indicated.7 Similarly, pos- ing stoves or other appliances unattended, or in-itron emission tomography (PET), functional MRI, volvement in automobile accidents.
assays of the cerebrospinal fluid for amyloid and tau Advance directives, durable power of attorney, proteins, and electrophysiological testing are prom- and stress on the part of caregivers must be ad-ising areas of research but are not indicated in the dressed. Training for caregivers in strategies to man- age daily activities, and referrals to day care, respitecare (short-duration residential care to relieve the Table 2. Atypical Early Features of Alzheimer’s Disease and Other Diagnostic
caregiver temporarily), home support services, coun- Considerations.
seling, and support groups can be very helpful, al-though such services are generally not covered by Diagnostic Consideration
Medicare or other insurance carriers. Several local and national organizations are excellent sources of information that may be useful to clinicians and fam- ilies, including the Alzheimer’s Association (http://www.alz.org or 800-272-3900) and the Alzheimer’s Disease Education and Referral Center (http://www.
alzheimers.org or 800-438-4380). Although the available data are not consistent, there is evidence that these nonpharmacologic interventions canhelp prolong the period before admission to a nursing home25,26 and reduce depression, burden, anger, and fatigue on the part of caregivers.27-30 Cholinesterase inhibitors are the drugs that haveproven most effective for the primary treatment of Alzheimer’s disease, and four — tacrine, donepezil,rivastigmine, and galantamine — are currently ap- Progressive supranuclear palsyWernicke’s encephalopathy proved by the Food and Drug Administration (FDA)for this indication (Table 3). These drugs presum- Downloaded from www.nejm.org on April 10, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2003 Massachusetts Medical Society. All rights reserved. ably act by increasing the availability of acetylcho- gressiveness and agitation.31-33 Patients who areline, the loss of which is the primary neurotrans- treated have a decline that parallels that of patientsmitter deficit in Alzheimer’s disease.
who receive placebo, although performance gener- Cholinesterase inhibitors typically result in a ally remains better with treatment than without small improvement in symptoms, followed by an treatment for at least one year.34-37eventual decline to a level below base line — a pat- If side effects develop, a switch in medications tern that corresponds to a two-to-seven-month de- can be accomplished relatively quickly; the use oflay in symptomatic progression. Virtually all studies the new medication can generally be initiated 24of cholinesterase inhibitors to date have involved hours after the discontinuation of the first one. Datapatients with mild-to-moderate Alzheimer’s disease are lacking on the benefit of switching to a differ-(range in MMSE score, 10 to 26). Patients treated ent agent in a given class if one such agent appearswith these agents may appear more alert and atten- ineffective. There are also limited data on the effica-tive and may have moderate improvements in mem- cy of cholinesterase inhibitors in patients with se-ory, language, and the activities of daily living, such vere dementia or dementias other than Alzheimer’sas dressing. In addition, cholinesterase inhibitors disease (such as vascular dementia or dementia withmay reduce behavioral disturbances, such as ag- Lewy bodies). Some studies, however, have suggest- Table 3. Medications Useful for the Treatment of Symptoms of Dementia.
Symptom and Drug
Initial Dosage
Recommended Final Daily Dose
Common Side Effects
Cognitive loss
8–12 mg twice a day (with food) Nausea, vomiting, weight Depression
Agitation, delusions,
or hallucinations
* This agent is contraindicated in patients with known hypersensitivity to it. It should be used with caution in patients with cardiac-conduction disease, hepatic or renal disease, asthma, peptic ulcer disease, or seizure disorders.
† Serum levels of hepatic enzymes (e.g., alanine aminotransferase) should be checked every 2 weeks for 16 weeks and then ‡ This agent is available as an oral solution.
§ This agent is contraindicated in patients with Parkinson’s disease.
¶ This agent has been associated with an increased risk of stroke.
Downloaded from www.nejm.org on April 10, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ed that cholinesterase inhibitors may also improve nonsteroidal antiinflammatory drugs, and predni-cognition and behavior in these patients.38,39 sone offer benefit in the treatment of Alzheimer’s The use of antioxidants is another approach to disease.46-49 Recent data from the Women’s Health treatment. Antioxidants presumably work by re- Initiative Memory Study50 indicate that therapy with
ducing free-radical production and oxidative inju- a combination of estrogen and progesterone may
ry to the brain. The results of a randomized, double- increase the risk of dementia, including Alzheimer’s
blind, two-year clinical trial involving 341 patients40 disease.
suggested that either vitamin E (alpha-tocopherol
at a dose of 1000 IU twice a day) or selegiline (a se- treatment of secondary symptoms
lective monoamine oxidase inhibitor) was benefi- For virtually all patients with Alzheimer’s disease,
cial for patients with moderately severe Alzheimer’s the symptoms extend beyond cognitive loss. De-
disease; both of these medications delayed the time pression occurs in 25 to 50 percent of patients, ag-
to clinically meaningful end points, including in- itation in 50 to 70 percent, and psychotic symptoms
stitutionalization and deficits in activities of daily such as paranoid delusions and hallucinations in
living, such as the ability to bathe and dress. On av- 30 to 60 percent. Treatment of these symptoms can
erage, treated subjects reached these end points improve the quality of life for both the patient and
six to nine months later than those given placebo.40 the caregiver. In addition to nonpharmacologic
There was no improvement in cognition, and the management, the use of medications should be con-
combination of these agents offered no additive sidered, although drugs for these symptoms have
benefit. Vitamin E is recommended more frequently not been approved by the FDA specifically for treat-
than selegiline because it is less expensive and has ment in patients with dementia.
fewer side effects.
In randomized clinical trials,51-57 haloperidol Studies have suggested that antiglutamatergic and the atypical antipsychotic agents risperidone therapy may be useful for treating Alzheimer’s dis- and olanzapine, when compared with placebo, re-ease and vascular dementia by limiting the neuro- duced the rates of agitation, delusions, and hallu-nal damage that may result from excessive release cinations by about 20 to 30 percent. Atypical anti-of glutamate.41,42 In one recent study,41 patients psychotic agents may be better tolerated than thewith Alzheimer’s disease who had moderate-to- older, traditional antipsychotic drugs, such as halo-severe dementia (MMSE score, <8) and were treat- peridol. Side-effect profiles should guide the choiceed with memantine, a noncompetitive N-methyl- of agents (Table 3).44 Similarly, antidepressant d-aspartate–receptor antagonist, for a seven-month agents (including sertraline, citalopram, and flu- period had improvements in ratings of severe im- oxetine) have improved depressive symptoms andpairment, scales of clinical impression, and activ- irritability in persons with dementia.58-60 Sedativeities of daily living.41 Memantine, as compared with antidepressants (e.g., paroxetine) or antipsychoticplacebo, delayed symptomatic progression by ap- medications (e.g., quetiapine) frequently improveproximately two months, and there were no signif- sleep disorders and nocturnal agitation, thereby cir-icant differences between the two groups in the over- cumventing the need for sleep medications, whichall rate of adverse events. At present, this treatment may further compromise cognition.
remains experimental in the United States, althoughit is available in some other countries. No data are yet available on its use for milder dementias.
Data on the efficacy of Ginkgo biloba for treating The response to medications for the treatment of dementia are limited and come largely from small primary and secondary symptoms of Alzheimer’sor open-label studies. The effect size in the few ran- disease is not predictable, and the choice of dosagedomized trials that are available is generally less and the duration of treatment rely on clinical judg-than the effect size associated with acetylcholin- ment. Definitive diagnostic tests remain to be devel-esterase inhibitors,43-45 but ginkgo remains a pos- oped. Appropriate therapy for patients with mildsible treatment option. As with all dietary supple- cognitive impairment is unclear, although studiesments, the purity and potency of the preparations are in progress. For the primary prevention of Alz-used may not be known.
heimer’s disease, data from randomized clinical Several large trials have failed to show that estro- trials are necessary to evaluate putative protective gen (alone or in combination with progesterone), factors identified in observational studies.61 Pro- Downloaded from www.nejm.org on April 10, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2003 Massachusetts Medical Society. All rights reserved. tective factors may include diet and exercise andthe use of estrogen (preparations without proges- Table 4. Guidelines for the Diagnosis and Management of Dementia.*
terone), nonsteroidal antiinflammatory drugs, anti- Diagnosis of dementia
oxidants, cholesterol-lowering agents, and ginkgo.
For the treatment of dementia, several other strat- National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association egies are currently under investigation, including the use of glutamate antagonists other than meman- Diagnostic and Statistical Manual of Mental Disorders, third edition (revised).
tine, calcium-channel blockers, cholesterol-lower- ing agents, antioxidants other than vitamin E, and Either computed tomography or magnetic resonance imaging is recom- mended for the initial evaluation; no other imaging procedure is rec- combination therapy (cholinesterase inhibitors and antiglutamatergic agents). Clinical trials of immu- Currently, no test for genetic markers is recommended.
notherapy with beta amyloid (so-called vaccination) Screening for depression, vitamin B deficiency, and hypothyroidism were halted last year after encephalitic reactions de- Screening for syphilis is not justified unless there is a clinical suspicion of veloped in several patients,62 but new formulations may soon be available for clinical investigation.
Management of dementia
Standards
Use of cholinesterase inhibitors should be considered in patients with mild-to-moderate Alzheimer’s disease, although the average benefit is limited.
Guidelines for the diagnosis and management of Estrogen should not be prescribed to treat Alzheimer’s disease.
Alzheimer’s disease have been developed by many Antipsychotic agents should be used to treat agitation and psychosis when environmental manipulations fail.
organizations, including the American Academy Behavior modification and scheduled toileting are helpful to reduce uri- of Neurology (summarized in Table 4) (http:// www.aan.com/professionals/practice/guidelines.
Use of vitamin E should be considered in an attempt to slow the progres- cfm),7,14,44 the American Psychiatric Associa- tion (http://www.psych.org/clin_res/pg_dementia.
Use of antidepressant medications should be considered for patients with cfm),63 the American Academy of Family Physi- Educational programs can be supportive for caregivers and nursing-home cians,64,65 and a consortium of the American As- sociation for Geriatric Psychiatry, the Alzheimer’sAssociation, and the American Geriatrics Society * The guidelines are based on those of the Quality Standards Subcommittee of (http://www.americangeriatrics.org/products/ positionpapers/aan_dementia.shtml).66 All endorsethe use of cholinesterase inhibitors and the treat-ment of coexisting conditions, if clinically indi- location of the car. For some patients, examina-cated. They also emphasize nonpharmacologic ap- tion of global mental status (e.g., with the MMSE)proaches for patient care.
is adequate for ascertaining the presence or pro-gression of dementia. However, patients with milddisease and with a high level of functioning at base line (such as the woman in the vignette), as well as younger patients or those with atypical symptoms, The diagnosis and management of memory loss are may require referral to a neuropsychologist forclinical challenges that require considerable time more extensive psychometric testing.
from busy health care providers. There are no bio- Forms for reliable instruments such as the logic markers for Alzheimer’s disease or most oth- MMSE, the Geriatric Depression Scale, and the In-er dementias, but with careful evaluation and the ap- strumental Activities of Daily Living tool can beplication of well-defined, reliable clinical criteria, downloaded from links on the Alzheimer’s Associa-diagnosis can be made with a high level of accuracy. tion Web site (http://www.alz.org/resourcecenter/ A crucial component of the workup is careful resourcecenter.htm). Norms specific for age and testing of mental status, to distinguish among de- level of education for the MMSE are available atmentia, mild cognitive impairment, and normal ag- http://www.nemc.org/psych/mmse.asp.8 Nursesing. With regard to the patient in the vignette, nor- and other trained personnel can perform the cogni-mal aging is an unlikely possibility, given the history tive examinations, the costs of which are frequentlyof checkbook errors and forgetfulness about the reimbursable.
Downloaded from www.nejm.org on April 10, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine If testing confirms the presence of dementia, A caregiver should be encouraged to come to I would prescribe a cholinesterase inhibitor (Ta- all of the patient’s appointments to ensure the safeble 4), as I do for most patients with Alzheimer’s arrival of the patient, who perhaps should not bedisease at the time of diagnosis, with the expecta- driving, and to facilitate the accurate assessmenttion of moderate improvements in memory, think- of symptoms. In addition, the caregiver’s own leveling, and general alertness and a delay in the pro- of stress can be assessed. Follow-up visits at whichgression of symptoms. The benefit of vitamin E is informants are interviewed and the patient is givenless clear; I discuss the data with patients and fam- brief cognitive tests should take place every threeilies and leave the decision to them. Perhaps the to six months, at a minimum, and more frequent-most important intervention is the identification ly when there are behavioral problems or suddenand treatment of other disabling symptoms, such changes or when medications are being adjusted.
as depression, agitation, delusions, and sleep dis- Supported by grants from the National Institutes of Health (R01 orders. Overall, I try to minimize the use of med- AG08325, R01 AG21055, and P50 AG-16573) and by the Alzhei- mer’s Disease Research Center at the University of California, Irvine.
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