Variation at the apolipoprotein E (apo E) gene locus affects cholesterol concentrations, the risk for atherosclerosis and Alzheimer disease (AD), and is associated with longevity in Caucasians. We have determined apo E gene frequencies and effects on cholesterol levels in Khoi San (Bushmen) from South Africa. The frequency of the apo epsilon 4 allele (0.37), which confers dose-dependent susceptibility to atherosclerosis and AD in Caucasians, was twice as high, and apo E4 homozygotes were 3-5 fold more frequent in the Khoi San (approximately 10%) compared with Caucasians (2%-3%). No significant effect of apo E variation on cholesterol concentration was noted in this non-Westernized population with low plasma cholesterol (mean cholesterol 149 mg/dl). This suggests that Bushmen carry a heavy genetic burden for these late-onset disorders if exposed to a Western lifestyle.