Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations.

•Familial Alzheimer disease (FAD) mutations affect presenilin membrane integration.•The transmembrane domains around the catalytic site are vulnerable to changes.•All FAD mutations cause changes in the active site of the γ-secretase complex.•The FAD mutants lead to a complex processing pattern of the amyloid precursor protein.