APOE encodes apolipoprotein E, a critical protein involved in lipid transport and metabolism with significant implications for neurodegenerative disease risk. The gene exists in three major allelic variants (ε2, ε3, ε4) that differentially influence disease susceptibility. APOE functions primarily in cholesterol and lipoprotein metabolism, facilitating the transport of lipids between cells and tissues, particularly in the brain where it plays essential roles in synaptic integrity, neuroplasticity, and cerebrovascular function 1. The protein also participates in amyloid-β binding and clearance, with APOE isoforms showing distinct effects on amyloid pathology, tau-mediated neurodegeneration, and microglial responses 1. The ε4 allele represents the strongest genetic risk factor for late-onset Alzheimer disease, driving earlier and more abundant amyloid pathology, while ε2 confers protection 12. Beyond Alzheimer disease, APOE variants influence cardiovascular risk through effects on LDL-cholesterol levels, with ε4 associated with increased cardiovascular risk and ε2 potentially leading to type III hyperlipoproteinemia in homozygotes 3. APOE also affects diverse cellular processes including ferroptosis resistance in melanoma, where secreted ApoE protects invasive cells from ferroptosis-inducing agents 4. Several therapeutic approaches targeting APOE have shown promise in mouse models, including modulating APOE levels, enhancing lipidation, and blocking APOE-amyloid interactions, though clinical translation remains challenging 2.