Atherosclerotic cardiovascular disease is the leading cause of preventable death in economically developed societies due to the widespread prevalence of modifiable risk factors including elevated low-density lipoprotein and triglyceride levels, obesity, metabolic syndrome, hypertension, diabetes mellitus, cigarette smoking, and physical inactivity. The clinical manifestations of atherosclerosis result in a large number of surgical procedures including 400,000 coronary artery bypass procedures and 70,000 carotid artery revascularization procedures conducted yearly in the United States alone. The apolipoprotein ϵ4 allele has a worldwide prevalence of about 14% and 25.5% in the predominately European-derived population of the United States. The ϵ4 allele is associated with an increased need for cardiovascular surgery via its association with higher atherogenic LDL levels resulting in adverse events including myocardial infarctions. Possession of one or two ϵ4 alleles is also associated with a more robust systemic inflammatory response that might destabilize lipid-filled plaques with infiltrating macrophages and lymphocytes. Systemic inflammatory mediators induced by physiologically stressful cardiac operations requiring cardiopulmonary bypass, e.g., valve replacements, might cross the blood-brain barrier and aggravate the already enhanced tendency for brain microglial cell-mediated neuro-inflammatory responses in ϵ4 carriers. The literature on adults who carry the ϵ4 allele demonstrating increased cognitive deficits following cardiac surgery is mixed. Baseline differences in study populations might account for disparate results. Infants carrying the less common ϵ2 allele who undergo congenital heart defect repair operations display delayed neurodevelopment that manifests during infancy and into childhood.