Clinical Inquiries

Do patients at high risk of Alzheimer’s disease benefit from early treatment?

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EVIDENCE-BASED ANSWER

Yes, but the extent of the benefit is unclear. Treating patients with early-stage Alzheimer’s disease yields statistically significant, though perhaps not clinically significant, improvement in cognition and global function (strength of recommendation [SOR]: A, consistent evidence from multiple randomized controlled trials [RCTs]). In a few cases, it may delay loss of function and need for long-term care.

Treating patients with mild cognitive impairment (MCI)—the most likely precursor to Alzheimer’s disease—with cholinesterase inhibitors seems to have an initial, but perhaps unsustained, benefit over no treatment (SOR: B, inconsistent results from few trials). Withdrawing anticholinergic drugs from patients taking them promises to reduce symptoms of MCI, but is unlikely to reduce rates of Alzheimer’s (SOR: C, well-designed observational study).

Clinical commentary

Remember nondrug interventions
Jaqueline Raetz, MD
Departments of Family Medicine and Long-Term Care, University of Washington School of Medicine, Seattle

Clinicians often forget the many nonpharmacologic treatments for dementia, including exercise, cognitive stimulation, increased socialization, addressing polypharmacy, and optimizing nutrition. Diagnosing and managing comorbidities such as depression and cardiovascular disease are also important. Primary care physicians who care for the frail elderly should advocate these interventions. In the very elderly, who are all at high risk of developing Alzheimer’s disease, these measures may help prevent functional decline and reduce clinically apparent disease.

All patients diagnosed with early-stage Alzheimer’s disease, and possibly patients with MCI, should be offered a trial of pharmacotherapy. However—given the high cost of drug therapy, the modest improvement it produces in patients with Alzheimer’s dementia, and the lack of definitive evidence that it benefits patients with MCI—I wouldn’t advocate medication for asymptomatic patients at high risk of developing dementia.

Evidence summary

Alzheimer’s disease is characterized by deficits in memory and at least 1 other cognitive domain (aphrasia, apraxia, agnosia, or loss of executive function) accompanied by impaired function. As the US population ages, Alzheimer’s disease is likely to increase substantially in prevalence and cost, from its current 4.5 million people affected and $100 billion per year in direct expenses.1

Because the definition of Alzheimer’s precludes asymptomatic disease, “early” treatment implies either treating a precursor condition or treating before cognitive and functional impairment force the patient and family to seek medical care. The literature identifies 2 possible prodromal conditions: MCI and personality change. Personality change is proposed as a prodrome based only on a small study that diagnosed Alzheimer’s disease at autopsy, so this Clinical Inquiry doesn’t address it further.2

Therapy for MCI: A look at 3 interventions

MCI is a measurable memory deficit, more severe than normal aging changes (slower learning of new material and difficulty retrieving names and places) but not meeting criteria for dementia.3 Researchers differ on a more precise definition; some subdivide MCI into “MCI-amnestic type” and “MCI-multiple cognitive deficits type.”4 MCI progresses to Alzheimer’s disease in anywhere from 10% to 56% of patients.4,5

Three interventions may benefit patients with MCI:

  • cholinesterase inhibitors
  • exercise
  • discontinuation of anticholinergic drugs in patients taking them.

Two recent RCTs of donepezil6,7 and 1 of galantamine8 showed initial cognitive improvement in MCI patients. However, the only trial carried out for 3 years showed no persistent benefit at that time.6

Another study showed that moderate exercise—30 minutes 3 days a week—improves cognition in MCI patients.9

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Evidence-based answers from the Family Physicians Inquiries Network

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