Jun and colleaguesArticle determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk of AD associated withthese genes is influenced by APOE genotypes. They find that unadjusted CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; CI, 1.07-1.22 for SNP rs3818361), and PICALM (OR, 0.89; CI, 0.84-0.94 for SNP rs3851179) were associated with AD in white individuals. They confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4–positive subjects. Thus, APOE and PICALM synergistically interact.