APOE and Alzheimer disease: Given the evolutionary shifts of this gene, the APOE alleles present a pronounced stepwise effect (ε2 < ε3 < ε4), where the ε2 allele confers substantial protection for AD and the ε4 allele increases risk in European ancestry populations [ε4/ε4 odds ratio (OR):12.5], but not conclusively in other ethnic groups (Farrer et al., 1997; Tang et al., 1998; Reiman et al., 2020; Table 2).