Smith and Ashford present a compelling hypothesis on evolution of APOE alleles, namely that ɛ4 prevalence is mediated by immune selection pressure against enteric pathogens. While the ɛ3 allele is more prevalent today, it outcompetedɛ4 only relatively recently, as immune selection pressure for more effective immune responses to such pathogens was alleviated with transition to agrarian from hunter-gatherer lifestyles. Smith and Ashford’s hypothesis is intriguing in itself, but the implications for APOE ɛ4 function in Alzheimer’s disease are even more so and encourage greater focus on specific aspects of immunity in accounting for both ɛ4-mediated and general Alzheimer’s disease risk.

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