Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) ε4/ε4 genotype, when the ε3 allele mutated from the ancestral ε4, which elevates the risk of Alzheimer’s disease. Modern humans living today predominantly carry the ε3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ε4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host’s defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ε4 carriers, yet ε4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ε3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer’s disease.