APP and Alzheimer disease: Hardy and Selkoe (2002)’s amyloid hypothesis proposed that PSEN1 mutations initiate disease pathogenesis by increasing the production of Aβ42. PSEN1 functions as a catalytic subunit of γ-secretase, an intramembranous protease that cleaves APP. Although Aβ40 accounts for ∼90% of Aβ production, the minor Aβ42 product is more hydrophobic and is thought to nucleate Aβ aggregation, leading to amyloid plaque deposition in the AD brain (Borchelt et al, 1996; Duff et al, 1996; Hardy & Selkoe, 2002).