APP and Alzheimer disease: While AD commonly presents sporadically later in life (sAD), evidence for the amyloid hypothesis was drawn from observations that rare autosomal dominant missense mutations in the genes encoding APP, or presenilin 1 (PSEN1) or 2 (PSEN2), which form the catalytic region of the γ-secretase complex responsible for proteolytic cleavage of APP into Aβ peptides, lead to highly penetrant familial forms of early-onset AD (fAD) (Ertekin-Taner, 2007).