Alzheimer Disease: A Commonsense Approach to Evaluation and Management

THE CASE:

An 84-year-old woman presents with a 3-year history of slowly progressivememory impairment accompanied by functional decline. Thepatient lives alone but has been receiving an increasing amount of support from her 2 daughters,who accompany her to the appointment. The daughters first noticed that their mother was havingtrouble driving. About a year ago, she started forgetting family recipes. She also left food cookingon the stove unattended and burned several pans. Currently, the daughters are providing mealsand transportation, assisting with housework, and doing their mother's laundry. They have becomeincreasingly alarmed because she takes her medications only sporadically, despite the factthat they fill her pillboxes and call her regularly with reminders. Their chief concern is whether itis safe for their mother to continue to live alone.The patient feels that her memory problems are normal for her age. Other complaints includeinsomnia, chronic urge incontinence, and long-standing depression, for which she takesacetaminophen/diphenhydramine, tolterodine, and paroxetine, respectively.Examination reveals a mildly anxious but pleasant patient. There is no evidence of weightloss. Neurologic examination results are normal. Folstein Mini-Mental State Examination score is18/30. The patient is unable to organize a clock drawing.

What further steps are needed to identify the cause of thispatient's memory impairment?

Dementia is an increasingly commondisorder seen in primary carepractice. Approximately 4 million Americansare thought to have dementia; ofthese, approximately two thirds haveAlzheimer disease (AD). The main riskfactor for dementia is advancing age.The prevalence at 65 years is about 6%;at 85 years, it is nearly 30%.The criteria for dementia includea loss of memory and 1 or moreother cognitive abilities (such as language,calculations, orientation, andjudgment) and substantial impairmentin social or occupational functioning

(Table 1).

In patients withprobable AD, symptoms have an insidiousonset and progress gradually.

History.

It may be difficult to obtaina comprehensive history from apatient with suspected dementia;hence, a family informant plays a crucialrole. The informant must be interviewedseparately from the patient,because family members generallydownplay the seriousness of thesymptoms in the patient's presence.Informants may also be in denial ofthe patient's condition or misrepresenthis or her motives ("Of courseMom has stopped cooking; she'stired after 50 years."). An informantwho is the patient's spouse may becognitively impaired as well.Because many elderly personsare no longer active in the occupationalor social realm, questions mustbe geared toward identifying the patient'sdegree of impaired function.For example, has the patient stoppedgoing to bridge club because she canno longer understand the bidding, orstopped crocheting because she canno longer remember how to do thestitches?Once a determination of dementiahas been made, it is essential thatthe diagnosis be as specific as possible.AD is no longer considered a diagnosisof exclusion. Although a definitivediagnosis is possible only atthe time of autopsy, clinical history,characteristic decline, and absence ofreversible factors allow a diagnosis of probable AD to be made with nearly90% specificity.

Diagnostic tests.

Specific domainsof memory, language, orientation,and visual-spatial disturbanceare most frequently tested with the30-item Folstein Mini-Mental StateExamination. Although interpretationcan vary according to educationalbackground, a score below 24 in atypical high school graduate suggestscognitive dysfunction. Abstractthought is particularly vulnerable toAD. For this reason, it is useful to askan open-ended question, such as"How do you spend your day?" Avague but socially appropriate answer,such as "Oh, I keep busy," is characteristicof AD.Similarly, this patient's commentthat her memory problems are normalfor her age is a socially appropriatestatement that does not implyinsight. Patients who express insightinto their memory problem are lesslikely to have dementia and morelikely to be depressed.The physical examination in apatient with AD is often unrevealing.The neurologic examination resultsare usually normal; focal or motordeficits point to another cause. Laboratorystudies--such as a metabolicprofile and tests of thyroid functionand vitamin B

₁₂

level--may be orderedto rule out medical causes ofcognitive impairment. Other laboratorytests can be ordered as indicated--for example, a hepatic functiontest in a patient with a history of alcoholabuse.Controversy exists aboutwhether imaging studies of the headare warranted; a noncontrast CT scanor MRI is a reasonable test to rule outcerebrovascular disease. Other imagingmodalities, such as single photonemission computed tomography andpositron emission tomography, areused as research tools only. ApolipoproteinE genotyping and other geneticstudies are not clinically useful.Other disorders, such as depressionor delirium, must be ruled outand/or treated before a definitive diagnosisis made. If possible, discontinuemedications that have potentialanticholinergic side effects, to seewhether the sensorium clears.

Benefits of pinpointing thediagnosis.

There are at least 3 importantreasons to make a specific diagnosisof AD as early as possible. First,early recognition allows time to treatpatients before marked deteriorationbegins. Acetylcholinesterase inhibitors,which enhance cholinergic neurotransmission,moderately improvecognitive function and global performanceand should be offered toevery patient with suspected mild tomoderate AD if the workup for reversiblecauses has been unrevealing

(Table 2).

These agents prolong thetime the patient spends in the earlystages of the disease and ultimatelyslow the decline.Estimates of improvement varywidely; in 1 report, 15% to 26% of patientsshowed improvement and upto 80% were stable at 6 months.

¹

Allacetylcholinesterase inhibitors act byincreasing the availability of acetylcholineand therefore have similar efficacyand toxicity. Data suggest thatwhen these agents are discontinued,a precipitous drop in function occurs.Therefore, it is unclear when to discontinuetherapy. Many practitionersfeel that patients experience a greater degree or rate of decline if therapy isstopped and choose to continue themedication unless there is a clear reasonnot to do so--such as nausea,weight loss, noncompliance, or costconcerns.Memantine--a newly approvedN-methyl-D-aspartate receptor antagonist--is indicated for patients withmoderate to severe AD. A recentstudy of 322 patients with moderateto severe AD found that the combinationof memantine and stable doses ofdonepezil resulted in significantly betteroutcomes than placebo on measuresof cognition, activities of dailyliving, global outcome, and behavior.

²

The second reason to make thisdiagnosis as early as possible is that itallows the caregiver additional time todeal with all of the ramifications. Educatethe patient's family about expecteddisease progression and providesupport; agencies such as the Alzheimer'sAssociation (www.alzheimers.org or 800-272-3900) are good resources.Discuss with the caregiverbehavior problems, such as wanderingand agitation; ways of managingpotentially unsafe behaviors, such ascooking and driving; and financialmanagement.Finally, and perhaps most important,an early diagnosis allows the patientto participate in planning forthe future. Although discussions regardingend-of-life issues are nevereasy, preparing a living will and establishingdurable power of attorneyfor health care and finances can avertdifficult and perhaps costly decisionsin the future.

OUTCOME OF THIS CASE

The patient's laboratory evaluationand CT scan were unremarkable.The acetaminophen/diphenhydraminewas discontinued, becausediphenhydramine can exacerbate confusion.The antidepressant waschanged to sertraline, because paroxetineis somewhat more sedating andhas more severe anticholinergic sideeffects than other selective serotoninreuptake inhibitors.

¹

(Although tolterodineis an anticholinergic, it was providingsignificant benefit to the patient.It could be discontinued if necessary.)Treatment was initiated withdonepezil, 5 mg/d for 4 weeks; thedosage was then increased to10 mg/d. The patient's daughterswere instructed to supervise her medicationsmore closely. Referral wasmade to the Alzheimer's Associationfor education and information aboutsupport groups. The patient began2 days per week of adult day care. Advancedirective documents weredrawn up. After 8 weeks, the patientand her daughters all felt that the patient'sthinking was clearer and thatshe was "more like herself."

References:

REFERENCES:

1.

Geldmacher, David S.

Contemporary Diagnosisand Management of Alzheimer’s Disease.

Newtown,Pa: Handbooks in Health Care Co; 2001.

2.

Tariot PN, Farlow MR, Grossberg GT, et al.Memantine treatment in patients with moderate tosevere Alzheimer disease already receivingdonepezil: a randomized controlled trial.

JAMA.

2004;291:317-324.

3.

Kane RL, Ouslander JG, Abrass IB, eds.

Essentialsof Clinical Geriatrics.

5th ed. New York:McGraw-Hill; 2004.

4.

Kawas CH. Clinical practice. Early Alzheimer’sdisease.

N Engl J Med.

2003;349:1056-1063.

FOR MORE INFORMATION:

• Knopman DS, Boeve BF, Petersen RC. Essentialsof the proper diagnoses of mild cognitive impairment,dementia, and major subtypes of dementia.Mayo Clin Proc. 2003;78:1290-1308.
• Richards SS, Hendrie HC. Diagnosis, management,and treatment of Alzheimer disease: a guidefor the internist. Arch Intern Med. 1999;159:789-798.