PSEN2 encodes presenilin-2, the catalytic subunit of the gamma-secretase complex, a key protease responsible for intramembrane cleavage of integral membrane proteins including Notch receptors and amyloid-beta precursor protein (APP) 1. PSEN2 selectively cleaves substrates in late endosomal/lysosomal compartments, generating intracellular amyloid-beta with longer variants. Beyond its proteolytic function, PSEN2 holoprotein acts as a calcium-leak channel facilitating passive calcium movement from the endoplasmic reticulum to cytosol and regulates mitochondrion-ER membrane tethering, thereby modulating calcium shuttling between these organelles. PSEN2 mutations cause autosomal dominant early-onset Alzheimer disease (EOAD), with disease mechanisms centered on altered APP cleavage leading to increased amyloid-beta production 2. Among 304 Chinese EOAD patients, PSEN2 variants accounted for 2.0% of cases, with specific mutations (V214L, M239T) demonstrated to increase Aβ42 levels and Aβ42/Aβ40 ratios 3. Cerebral organoids derived from PSEN2 mutation carriers (N141I) exhibit AD-specific pathological markers including altered tissue patterning and premature neuronal differentiation 4. CSF biomarkers in PSEN2 mutation carriers show consistent abnormalities in tau, phospho-tau, and Aβ42 levels 2. PSEN2 variants also rarely contribute to dilated cardiomyopathy, indicating broader pathogenic significance beyond neurodegeneration.