Pathogenic Aβ generation in familial Alzheimer’s disease: novel mechanistic insights and therapeutic implications

•Increased Aβ42/43 to Aβ40 ratios are associated with most familial AD cases.•Altered γ-secretase–APP interactions/stabilities underlie pathogenic Aβ42/43 generation.•An atomic γ-secretase–APP structure allows insights into the first step of Aβ generation.•GSMs, advanced anti-Aβ drugs, lower Aβ42/43 in preclinical models for most familial AD mutants.•DIAN and API cohorts offer possibilities for future clinical trials with suitable GSMs.