Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments — UC Berkeley

Author summary The apolipoprotein ε4 (APOE ε4) allele is a major risk factor for Alzheimer’s dementia risk in industrialized countries, yet it persists at moderate frequencies around the world without strong evidence of being selected against. One explanation for this paradox is that ε4 is beneficial in certain environments—especially those more similar to the non-industrial contexts in which humans evolved—an idea which is encouraged by observations that APOE influences many biological processes from cholesterol processing to immune function. Indeed, prior studies in non-industrial settings have found immune and fertility benefits of ε4. We worked with two Indigenous groups who span wide lifestyle gradients—the Turkana of Kenya and the Orang Asli of Peninsular Malaysia—to study how APOE genotypes affect cholesterol, immunological, and reproductive traits across industrialization. First, as expected, we found that ε4 was strongly associated with higher LDL and total cholesterol. Second, we found weak but consistent evidence that ε4 was associated with lower systemic inflammation and mixed evidence that this effect was stronger in industrialized settings. Finally, we found little evidence that ε4 influenced female reproductive traits. Our results suggest that the effects of APOE ε4, and the other APOE genotypes, are consistent on cholesterol but highly context dependent on other traits.