PSEN1 and Alzheimer disease: The important role played by Aβ in AD pathogenesis led to the amyloid cascade hypothesis (Hardy and Higgins, 1992), based on the observation that early onset, familial forms of AD are associated with mutations in APP or presenilin 1 or 2 and that all appear to be associated with Aβ generation, deposition, or aggregation propensity (Levy et al., 1990; Van Broeckhoven et al., 1990; Chartier-Harlin et al., 1991; Goate et al., 1991; Hardy, 1991).