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The ϵ4 allele of the apolipoprotein E (APOE) gene is associated with increased cholesterol levels and heart disease. Population allele frequencies of APOE have previously been shown to vary, with ϵ4 frequencies generally increasing with latitude. We hypothesize that this trend resulted from natural selection protecting against low‐cholesterol levels. In high‐latitude cold environments and low‐latitude hot environments, metabolic rate is elevated, which could require higher cholesterol levels. To explore this hypothesis, we compiled APOE allele frequencies, latitude, temperature, and elevation from populations around the world. ϵ4 allele frequencies show a curvilinear relationship with absolute latitude, with lowest frequencies found in the mid‐latitudes where temperatures generally require less expenditure on cooling/thermogenesis. Controlling for population structure in a subset of populations did not …