Presenilin (PSEN1/PSEN2)

Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are nine-pass membrane proteins. They form the catalytic core of the gamma-secretase complex, together with nicastrin, APH-1, and PEN-2. Gamma-secretase cuts more than ninety target proteins from within the membrane. These targets include the amyloid precursor protein, Notch, N-cadherin, and ErbB4. PSEN1 mutations are the most common cause of inherited, early-onset Alzheimer's, usually striking before age 60. More than three hundred disease-causing PSEN1 variants have been reported. Most of them shift the cut toward the longer, stickier amyloid pieces that build up in your brain (Abeta42 and Abeta43). PSEN2 mutations are rarer, and usually bring a later, more variable onset. Carrier families have been key for mapping biomarker timelines. Cohorts like DIAN and the Colombian paisa kindred made that possible. This biology underpins the amyloid cascade hypothesis. That hypothesis gained renewed clinical weight with the approval of lecanemab (FDA 2023, EU 2025) and donanemab (FDA 2024, EU 2025) for early symptomatic Alzheimer's.

Last reviewed: June 22, 2026

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