Until 300,000 years ago, ancestors of modern humans were ubiquitously ε4/ε4, and then the ε3 allele mutated from the ancestral ε4 allele. All ε4 carriers lived in southern Africa until 70,000 years ago when some migrated to East Africa 60,000 years ago and then started the great migration out of Africa that settled the world. Early ε4 humans were under tremendous survival pressure, experiencing an infant and child mortality rate of >50% and short lifespans, with only about 10% living past 60. Chronic diseases like atherosclerotic manifestations and Alzheimer’s disease did not exert significant evolutionary pressure due to the short lifespans. As compared to ε3 carriers, these early ε4 carriers were adapted genetically to the high pathogen environment of Africa via higher fertility rates, more rapid infant development, a more robust innate immune response against bacteria and parasites, efficient hemostasis following traumatic injury, possible resistance against periodontal disease, and higher serum cholesterol levels that protected the infant brain during bouts of parasite- or bacteria-induced diarrhea. As ε4 carriers migrated out of the tropics to the temperate zones and into numerous microclimatic areas like islands, mountain valleys, and mountains, the pathogen ecosystem changed continuously and variably. For some infectious and chronic diseases, possession of an ε4 allele advantages survival, while for some other diseases, possessing an ε3 allele is advantageous. In general, the equatorial infectious disease burden is higher than that of the temperate zones—especially for parasitic diseases and bacterial infections. The current geographic distribution of the ancestral ε4 allele correlates with areas of high pathogen burden. In temperate zones with lower pathogen burdens, where the ε3 allele predominates, a more modest immune response might lessen the risk of adverse autoimmune responses or tissue damage from inappropriately sustained inflammation. In current ancestral populations living in areas with high but variable pathogen levels (San people, Pygmies, Fon, Zairians, Tutsi, New Guineans, Malaysian and Australian aborigines, Sami), diverse evolutionary selection pressures frequently concomitant with a high risk of traumatic injury have resulted in an admixture of the ancestral ε4 allele and the now more common ε3 allele.