APOE alleles and apolipoprotein E isoforms control plasma cholesterol level on population level. Among three 2, 3, 4 alleles, 4 allele is associated with the increase in cholesterol level, risk of atherosclerosis and Alzheimer disease, while 2 allele is associated with the decrease in cholesterol level and risk of atherosclerosis. The increase in plasma triglyceride is an independent risk factor of atherosclerosis and triglyceride–high density lipoprotein coupling determines the efficiency of reverse cholesterol transport. The impairment of this coupling specifically at hypertriglyceridemia may be followed by specific lipoprotein markers. The influence of major lipid-lowering drugs on lipoprotein metabolism and association of apoE isoforms with the efficiency of therapy by statins and fibrates are summarized both at isolated and combined increase in plasma triglyceride and cholesterol. APOE polymorphism seems to be a single genetic variant with a confirmed stratification both at candidate gene and at wide genome analyses.