Presenilin (PSEN1/PSEN2)

Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are nine-transmembrane proteins that form the catalytic core of the gamma-secretase complex together with nicastrin, APH-1 and PEN-2. Gamma-secretase performs intramembrane proteolysis of more than ninety substrates, including the amyloid precursor protein, Notch, N-cadherin and ErbB4. PSEN1 mutations are the most common cause of autosomal-dominant early-onset Alzheimer disease, typically with onset before age 60; more than three hundred pathogenic PSEN1 variants have been reported, most of which shift gamma-secretase cleavage toward longer, more amyloidogenic Abeta42 and Abeta43 species. PSEN2 mutations are rarer and usually associated with later, more variable onset. Carrier families have been pivotal for biomarker timelines through cohorts such as DIAN and the Colombian paisa kindred. The amyloid cascade hypothesis that this biology underpins gained renewed clinical relevance with the approval of lecanemab (FDA 2023, EU 2025) and donanemab (FDA 2024, EU 2025) for early symptomatic Alzheimer disease.