The neuropathologic finding that amyloid beta (Aβ) peptide, an APP protein cleavage product, is a component of amyloid plaques [2] and the observation that mutations in APP, and genes that affect APP cleavage: PSEN1 and PSEN2, [3–5], cause early onset AD suggested that APP plays a particularly important role in AD pathogenesis [6–9] and were the basis for the amyloid cascade hypothesis of AD [10–12]. Here, PSEN2 is linked to Alzheimer disease.