APP and Alzheimer disease: The Aβ hypothesis is supported by findings from genetics: (1) familial AD mutations of APP and PSEN1/2, transcripts encoding two key components of the γ-secretase complex, are involved in either Aβ generation or Aβ processing and result in excessive production of Aβ40–42 [33]; conversely, an APP missense mutation (A673T) results in a lifelong decrease in APP cleavage by β-secretase, offering a reduced clinical risk of AD [34]; (2) the epsilon4 allele of apolipoprotein E (ApoE) is the major genetic risk factor for sporadic AD, highly likely through the effects on Aβ metabolism [35].