title: Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease.
abstract: BACKGROUND
  The apolipoprotein E (APOE) ε4 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 ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 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 ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 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 ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 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 ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.
authors.affiliation: University of Alabama, Birmingham, Birmingham, AL, USA. Electronic address: rekenned@mail.ad.uab.edu.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Kennedy
authors.affiliation: University of Alabama, Birmingham, Birmingham, AL, USA.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Cutter
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D002986:Clinical Trials as Topic; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D003198:Computer Simulation; D016208:Databases, Factual; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use; D018579:Patient Selection; D012720:Severity of Illness Index
chemical_list: D053327:Apolipoprotein E4; D018697:Nootropic Agents
keywords: Alzheimer disease; Alzheimer's Disease Assessment Scale; Alzheimer's Disease Cooperative Study; Alzheimer's Disease Neuroimaging Initiative; Apolipoprotein E ε4; Biomarkers; Clinical trial simulations; Clinical trials; Mild cognitive impairment