Pharmacotherapy of Alzheimer disease

Objective: To systematically review published clinical trials of the pharmacotherapy of Alzheimer disease (AD). Method: We searched MEDLINE for published English-language medical literature, using Alzheimer disease and treatment as key words. No other search engine was used. Our review focused on randomized clinical trials (RCTs) and corresponding metaanalyses. Results: Although there are many RCTs for the treatment of mild cognitive impairment (MCI), none have been successful in their primary analysis. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in 3- to 12-month placebo-controlled RCTs assessing cognitive, functional, behavioural, and global outcomes in patients with mildly to moderately severe AD. Recent data from patients with severe stages of AD demonstrate the efficacy of donepezil on cognitive and functional measures but not on behaviour. The N-methyl-D-aspartate receptor antagonist memantine has been demonstrated to be effective in 6-month, placebo-controlled RCTs of 6 months duration assessing cognitive, functional, and global outcomes of inpatients with moderate-to-severe AD (defined as a Mini Mental State Examination score below 20). Post hoc analyses have demonstrated a benefit in regard to agitation and (or) aggression, but this needs to be confirmed in a prospective RCT across Canada. Disease-modifying treatments are being tested in mild stages of AD in 18-month RCTs with cognitive and global outcomes as primary efficacy outcomes, primarily with drugs reducing amyloid synthesis or aggregation. Successful treatment in mild stages of AD could lead to RCTs in MCI and, possibly, in genetically high-risk asymptomatic individuals. Conclusion: The significant advances in the symptomatic pharmacotherapy of AD may be followed by disease-modification treatments.