Apolipoprotein E ε3/ε4 and coronary artery disease: lipid and non-lipid mechanisms in personalized prevention — narrative review

Background Coronary artery disease (CAD) remains a leading cause of cardiovascular morbidity and mortality worldwide. Although traditional risk factors—including dyslipidemia, hypertension, diabetes mellitus, obesity, and smoking—account for a substantial proportion of CAD risk, they do not fully explain interindividual differences in disease onset, progression, or severity. Apolipoprotein E (ApoE) is a multifunctional protein involved in lipoprotein metabolism, inflammatory regulation, oxidative balance, endothelial function, and tissue repair. The APOE gene harbors three major alleles— ε 2, ε 3, and ε 4—generating six common genotypes. Among these, the ε 3/ε4 genotype has been associated in several studies with an unfavorable lipid profile and increased susceptibility to CAD and premature CAD. Objective This narrative review synthesizes current evidence on the association between the APOE ε 3/ε4 genotype and CAD, with emphasis on lipid-mediated and non-lipid biological mechanisms, interactions with conventional cardiovascular risk factors, and potential implications for personalized cardiovascular prevention. Throughout the review, evidence obtained directly in ε3/ε4 carriers is distinguished from evidence extrapolated from ε4-carrier, ε4/ε4, or overall APOE-polymorphism analyses. Methods A narrative literature search was conducted in PubMed, Embase, Scopus, and Web of Science from database inception to August 2026, using the terms “Apolipoprotein E,” “APOE ε3/ε4,” “APOE polymorphism,” “coronary artery disease,” “premature coronary artery disease,” “lipid metabolism,” “atherosclerosis,” and “cardiovascular genetics.” English-language original articles, narrative reviews, and meta-analyses relevant to the APOE ε3/ε4 genotype and cardiovascular disease were included. Retrieved studies were classified by genotype contrast and by level of evidence (human observational, human interventional, or experimental). Summary ApoE plays a central role in plasma lipoprotein transport and hepatic clearance of triglyceride-rich lipoprotein remnants. The ε 4 isoform has been associated with higher LDL cholesterol, apolipoprotein B, and remnant-lipoprotein concentrations, which may partly explain its association with coronary atherosclerosis. Beyond lipid transport, ApoE modulates macrophage activity, inflammatory signaling, oxidative stress, endothelial function, apoptosis, angiogenesis, and tissue repair. These non-lipid pathways derive predominantly from in vitro and animal models and remain unvalidated in human ε3/ε4 carriers. Where adjusted, ε3/ε3-referenced estimates are available, the effect size is modest, with odds ratios of approximately 1.5 for unselected CAD and 1.5–2.2 for premature coronary phenotypes. Conclusions The APOE ε 3/ε4 genotype may represent a genetic modifier of CAD risk, particularly when combined with traditional cardiovascular risk factors. Current evidence remains heterogeneous, and APOE genotyping should be regarded as a potential adjunctive marker and not a stand-alone risk prediction tool; this is distinct from its established diagnostic role in dysbetalipoproteinemia. Prospective studies integrating genetic, lipid, inflammatory, and imaging data are needed to clarify its incremental clinical value beyond LDL-C, apolipoprotein B, lipoprotein(a), and coronary artery calcium.