The Mechanism of ApoE Gene Polymorphisms in Alzheimer's Disease

Abstract

Apolipoprotein E (ApoE) is a core regulator of lipid homeostasis in the central nervous system. Its genetic polymorphisms differ in key amino acid residues (ε2: Cys112/Cys158; ε3: Cys112/Arg158; ε4: Arg112/Arg158), which can significantly alter ApoE’s lipid-binding capacity, affinity for the low-density lipoprotein receptor (LDLR) family, and lipid transport efficiency, thereby profoundly affecting the pathogenic risk and pathological progression of Alzheimer’s disease (AD) --- the ε4 allele can increase AD risk by 2.35-4.55 times, the ε2 allele reduces the risk, and the ε3 allele serves as a neutral reference isoform. Integrating recent clinical and basic research, this paper systematically expounds on the molecular structural characteristics of ApoE (including the N-terminal receptor-binding domain, C-terminal lipid-binding domain, and hinge region) and the intracerebral lipid transport pathway, analyzes the conformational differences of the three isoforms, and clarifies the four key pathological mechanisms by which ApoE4 induces AD through lipid transport deficits, aiming to provide precise theoretical support for AD interventions targeting the lipid transport function of ApoE.