Apolipoprotein E (ApoE) is a glycoprotein with three major isoforms (E2, E3, E4) that mediates lipid transport by binding low-density lipoprotein receptors (LDLR, LRP, VLDLR) to facilitate cholesterol redistribution. Its receptor-binding domain (residues 140–150), rich in lysines and arginines, enables interactions critical for lipoprotein clearance and lipid homeostasis. Beyond lipid metabolism, ApoE modulates immune responses by suppressing T-cell activation via reduced MHC class II expression on antigen-presenting cells and influences neurobiology through astrocyte-derived cholesterol transport to neurons. Elevated ApoE levels (normal plasma: ~5 mg/dL) are observed during peripheral nerve injury, where it aids tissue repair by coordinating lipid reutilization; however, the E4 isoform delays regeneration and neuromuscular reinnervation.

Clinically, ApoE2 homozygosity or mutations like Arg145Cys cause familial type III hyperlipoproteinemia, characterized by β-VLDL accumulation and xanthomas. The ε4 allele is a major genetic risk factor for Alzheimer’s disease, promoting Aβ aggregation and impairing synaptic function. ApoE4 also exacerbates cardiovascular risk by elevating LDL-C and carotid intima-media thickness. Emerging roles include modulating melanoma cell states, where ApoE secretion by MITF-high tumors confers ferroptosis resistance via lipid peroxidation suppression.