APOE and Alzheimer disease: These and other discoveries, including the role of the apolipoprotein E ε4 (APOE ε4) gene in increasing the risk of both amyloid aggregation and clinical AD, and the effects of amyloid induction of tau hyperphosphorylation, reduction in cerebral glucose metabolism, and brain atrophy eventually led to the “amyloid hypothesis” of AD proposed by Hardy and Allsop [4] and later updated by Selkoe [5].