APOE and Alzheimer disease: As mentioned earlier, among the risk loci for AD, APOE is the most robust factor for AD pathogenesis.120 Unlike other isoforms, APOE4 may increase Aβ by decreasing its clearance121–123 and enhancing tau hyperphosphorylation.124–126 GSK3 is one of the upstream factors that jointly regulates Aβ and tau.