The amyloid cascade hypothesis (or the amyloid hypothesis) has been the predominant AD theory for decades (Hardy and Higgins, 1992; Hardy and Selkoe, 2002; Selkoe and Hardy, 2016), having emerged through the identification of amyloid-β (Aβ) as the plaque-forming peptide from AD and Down syndrome brains ∼35 years ago (Glenner and Wong, 1984a, b), which allowed the subsequent identification of APP as the gene locus responsible for Aβ (Goldgaber et al., 1987; Tanzi et al., 1987b). The gene discussed is APP; the disease is Down syndrome.