APOE encodes apolipoprotein E, the major lipid and cholesterol carrier in the central nervous system 1. Primary function involves cholesterol metabolism and lipoprotein transport, with the APOE gene exhibiting three major polymorphisms (ε2, ε3, ε4) that critically influence disease risk 2. Mechanism: APOE modulates Alzheimer's disease pathogenesis through multiple pathways beyond amyloid-β metabolism. The ε4 allele drives earlier and more abundant amyloid pathology 2, while APOE regulates tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier integrity 3. APOE influences amyloid-responsive microglia populations, with ε4 carriers showing depleted CD163-positive microglia 4. Additionally, APOE genotype shapes gut microbiome composition and butyrate-producing bacteria abundance, potentially affecting neuroinflammation 5. Disease relevance: APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease and increases cardiovascular disease risk through elevated LDL cholesterol 6. APOE ε2 provides protective effects. Rare APOE variants contribute to familial dyslipidemia and autosomal dominant hypercholesterolemia 6. APOE impacts other neurodegenerative diseases including Parkinson's disease, traumatic brain injury, and multiple sclerosis 1. Clinical significance: No APOE-directed therapies currently exist despite preclinical success with level modulation, lipidation enhancement, and isoform switching approaches in mouse models 3.