Mutations in the PSEN1 gene, encoding presenilin-1 (PS1), are the most common cause of familial Alzheimer’s disease (FAD). PS1 functions as the catalytic subunit of γ-secretase, an intramembranous protease that cleaves a variety of type 1 transmembrane proteins, notably including the amyloid precursor protein (APP) and Notch. Following prior cleavage by β-secretase, processing of APP by γ-secretase generates β-amyloid (Aβ) peptides of varying lengths. Whereas 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. In PNAS, Sun et al.(1) used an in vitro system to evaluate the effects of 138 pathogenic mutations in PSEN1 on the production of Aβ40 and Aβ42, and their findings provide valuable perspectives on pathogenic mechanisms in AD. The authors’ systematic analysis of mutations affecting all PS1 residues altered in FAD provides an unprecedented perspective on the impact of PSEN1 mutations on Aβ production and γ-secretase activity. The mechanism by which PSEN1 mutations lead to neurodegeneration and dementia in FAD remains hotly debated. Two distinct but not mutually exclusive hypotheses have been proposed to explain how PSEN1 mutations cause FAD (2, 3). The amyloid hypothesis proposed that PSEN1 mutations initiate disease pathogenesis by increasing production of Aβ42 (2). This view was based on initial studies in which small numbers of clinical PSEN1 mutations were found to increase levels of Aβ42 in plasma of FAD patients, transfected cells, and transgenic mice, leading to the notion that PSEN1 mutations triggered FAD pathogenesis by enhancing APP processing and inducing excessive production of Aβ42 (2, 4–6). As inconsistencies with this model subsequently emerged, revision of the amyloid hypothesis shifted the focus to relative rather than absolute increases in Aβ42 production, and the ability to increase the Aβ42/Aβ40 ratio has been widely considered an essential and invariant property of PSEN1-bearing pathogenic mutations (7). The presenilin hypothesis offers an alternative view of disease pathogenesis, proposing that PSEN1 mutations cause a loss of essential presenilin functions in the brain, which in turn triggers neurodegeneration and dementia in FAD (3). This proposal was prompted by earlier genetic findings showing that presenilin is essential for learning and memory, as well as neuronal survival during aging in the adult mouse cerebral cortex (8–10), and was further supported by more recent reports demonstrating that PSEN1 mutations typically cause loss of PS1 function (11, 12) and that severe PSEN1 mutations abolished γ-secretase activities and Aβ production in mouse brains (13, 14).