Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

Background: The apolipoprotein E (APOE) 64 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents. Methods: We tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE 64 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE 64 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. Results: Enrichment of clinical trial participants based on APOE 64 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE 63 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. Conclusions: Although samples enriched for APOE 64 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE 64 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE epsilon 4/epsilon X (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action. (C) 2014 The Alzheimer's Association. All rights reserved.