The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.