PSEN1 encodes presenilin 1, the catalytic subunit of the gamma-secretase complex that cleaves integral membrane proteins including APP and Notch receptors 1. As part of this multiprotein complex, PSEN1 regulates amyloid-beta generation and multiple signaling cascades critical for neural development 1. Beyond proteolysis, PSEN1 functions as a calcium-leak channel regulating endoplasmic reticulum-to-cytosol calcium flux and modulates cell-cell adhesion through E-cadherin stabilization 1. PSEN1 mutations cause early-onset Alzheimer's disease (EOAD), accounting for ~5-10% of AD cases, with over 300 pathogenic variants identified 1. Mechanistically, PSEN1 mutations shift APP processing toward amyloidogenic Aβ42 production and impair autophagy and chaperone responses 2. Disease manifestations extend beyond classical EOAD: atypical phenotypes include spastic paraparesis, seizures, visual impairment, frontotemporal dementia, Parkinson's disease, and dementia with Lewy bodies 3. Non-neurodegenerative phenotypes associated with PSEN1 mutations include acne inversa and dilated cardiomyopathy 34. Genetic modifiers appear critical in determining disease onset age and clinical presentation 1. Recent studies using cerebral organoids and single-nucleus sequencing reveal premature neuronal differentiation and dysregulated chaperone-mediated autophagy in PSEN1-mutant cells 52, providing insights for therapeutic development.