“…Mutations in APP and in genes that regulate APP processing, such as the ␥-secretase components PSEN1/PSEN2 and BRI2/ITM2B, cause FAD and the AD-like familial British dementia and familial Danish dementia (Matsuda et al, 2005(Matsuda et al, , 2008(Matsuda et al, , 2011aGiliberto et al, 2009;Garringer et al, 2010;Tamayev et al, 2010aTamayev et al, ,b, 2011Tamayev et al, , 2012bDe Strooper and Voet, 2012). Increased BACE1 expression/activity and BACE1 gene polymorphisms are associated with SAD (Jo et al, 2008;Hampel and Shen, 2009;Cheng et al, 2014;Long et al, 2014); loss-of-function mutation in genes coding for proteins with ␣-secretase activity are associated with SAD (Suh et al, 2013;Hartl et al, 2018). This genetic evidence, coupled to the identification of A as the main component of senile plaques, provides the foundation for the "amyloid hypothesis," which states, briefly, that A is the toxic metabolite responsible for neurodegeneration in AD.…”