Divergent Biological Consequences of APOE Isoforms Across Industrialized and Non-Industrial Environments

The apolipoprotein {varepsilon}4 (APOE {varepsilon}4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE {varepsilon}4--which is ancestral in humans--has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE {varepsilon}4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE {varepsilon}4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia--two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles--we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that more APOE {varepsilon}4 alleles are associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that more APOE {varepsilon}4 alleles are correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE {varepsilon}4; however, we find that APOE {varepsilon}4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.