Background: Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with nicastrin (NCT), anterior pharynx-defective protein 1 (APH1), and presenilin enhancer 2 (PEN2), the catalytic subunit PS1 constitutes the core of the c-secretase complex and contributes to the proteolysis of the amyloid precursor protein (APP) into amyloid-beta (A beta) peptides. Although there is a growing consensus that FAD-linked PS1 mutations affect Ab production by enhancing the A beta 1-42/A beta 1-40 ratio, it remains unclear whether and how they affect the generation of APP intracellular domain (AICD). Moreover, controversy exists as to how PS1 mutations exert their effects in different experimental systems, by either increasing A beta 1-42 production, decreasing A beta 1-40 production, or both. Because it could be explained by the heterogeneity in the composition of gamma-secretase, we purified to homogeneity complexes made of human NCT, APH1aL, PEN2, and the pathogenic PS1 mutants L166P, Delta E9, or P436Q.