Alzheimer disease: Time to improve its diagnosis and treatment

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Key warning signs

The Alzheimer’s Association17 lists 10 key warning signs of Alzheimer disease:

  • Memory loss
  • Difficulty performing familiar tasks
  • Problems with language
  • Disorientation to time and place
  • Poor or decreased judgment
  • Problems with abstract thought
  • Misplacing things
  • Changes in mood or behavior
  • Changes in personality
  • Loss of initiative.

As annotated on the Alzheimer’s Association Web site,17 the list also highlights key differences between normal aging and more serious symptoms of possible Alzheimer disease. For example, patients with Alzheimer disease are more likely to forget entire experiences and not remember them later, whereas normal elderly may forget parts of events and then recall the missing details later. Also, patients with Alzheimer disease are more likely to lose the ability to complete familiar tasks or to follow written or spoken directions. Additional signs that a more serious cognitive problem exists include misplacing items so often that it interferes with daily activities, frequently losing the thread of conversations, and repeating the same questions, stories, or comments within a short time without being aware of it.18

The key factor differentiating mild cognitive impairment from dementia is that the former does not significantly disrupt the ability to perform activities of daily living,4 although some mild degree of impairment in complex instrumental activities of daily living is likely present.19Table 1 highlights some of the considerations discussed here for differentiating normal aging from mild cognitive impairment and Alzheimer disease.

Talk to a family member

Interviewing a reliable informant who knows the patient well is extremely helpful for determining the presence and extent of a cognitive problem. This is particularly important because even patients with mild cognitive impairment may have impaired awareness of their memory problems and may underestimate20 or overestimate21 the problem.

Ask the informant about symptoms such as being repetitive, misplacing items, or having trouble with finding words or names, remembering to take medication, managing finances, navigating while driving, or performing multiple tasks or all steps of a task. A change in behavior may be the first sign of a cognitive disorder, so the patient and informant should also be asked about signs of irritability, anxiety, increased social isolation, and decline in motivation.

Screening tests

Memory can be tested with a three- or four-word recall test during the physical examination, with the addition of a clock-drawing task,22 or can be assessed with a composite cognitive measure. For example:

The Mini-Mental State Exam (MMSE)23 can be given by the clinician or a trained member of the office staff. People with Alzheimer disease show progressive disability and a predictable rate of decline of approximately 2.8 points on the MMSE per year, with slower decline in the milder stages and faster decline in the moderate and severe stages of the illness.

The Montreal Cognitive Assessment Battery (MOCA,,24 is a new cognitive screening test with a 30-point format similar to that of the MMSE. It includes a five-word recall, clock-drawing, and executive and visuospatial items that make it more sensitive for mild cognitive impairment and vascular dementia.

The Alzheimer’s Disease 8 (AD8),25 a sensitive eight-question scale developed at Washington University, St. Louis, MO, can be completed by an informant in the waiting room.

New computerized screening measures are being developed that can be completed online or in the waiting room, and some simulate practical tasks such as using an automated teller machine and driving.

Care should be taken when interpreting performance on screening tests in patients who have very low or very high education levels, who are not tested in their native language, or who have physical or sensory deficits that might limit their performance.

Brain imaging and other tests

Patients with evidence of cognitive impairment should undergo a structural brain imaging test such as noncontrast computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate for changes consistent with Alzheimer disease and to help rule out alternative causes of the cognitive impairment.26,27

Neuropsychologic testing can be done by a dementia specialist, who can also help with diagnosis and treatment.

Positron emission tomography (PET) using fluorodeoxyglucose shows patterns of brain metabolism and can help differentiate Alzheimer disease from non-Alzheimer dementia, as patients with the former typically show hypometabolism in the temporal and parietal cortices.28

Quantitative MRI and PET amyloid imaging are exciting new techniques currently being developed to diagnose Alzheimer disease earlier in clinical practice.29,30

Cerebrospinal fluid markers. A decrease in the amyloid beta 1–42 peptide and an increase in the tau and phosphotau proteins may be the earliest signs of Alzheimer disease.31,32 However, before these tests can be widely used in clinical practice, their sensitivity and specificity need to be established, people’s reluctance to undergo lumbar puncture will have to be overcome, and third-party reimbursement will have to be obtained.

Genetic factors also play an important role in the development of Alzheimer disease. The apolipoprotein E4 (ApoE4) allele is a marker for Alzheimer disease. People of European descent who possess one copy of the allele have three times the risk (with onset typically in their 70s), and individuals who are homozygous have 15 times the risk (with typical onset in their 60s), compared with people lacking ApoE4.33,34 This test is commercially available but is still considered a research tool.

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