APOE and familial Alzheimer disease: Genetic evidence supports this hypothesis, with APP (amyloid precursor protein), PSEN1, and PSEN2 (encoding two catalytic subunits of γ -secretase) mutations linked to early-onset familial AD (FAD) [16,17], while late-onset sporadic AD (SAD) is associated with the APOE ε4 (apolipoprotein E ε4) allele, impaired Aβ clearance, and increased BACE1 (β—secretase 1, β-site amyloid precursor protein cleaving enzyme 1) [18,19,20,21,22] (Figure 1).