APOE ε4’s Health Effects Flip Depending on Where and How People Live

For decades, the APOE ε4 allele has carried one of the worst reputations in human genetics. Carrying one or two copies of this variant of the apolipoprotein E gene is one of the strongest known genetic risk factors for Alzheimer’s disease, and it is also linked to elevated cholesterol and greater cardiometabolic disease in industrialized populations. Yet ε4 is the ancestral form of the gene, carried by a substantial fraction of people across the globe and retained through millions of years of human evolution. That paradox has long puzzled evolutionary biologists and geneticists alike: why would natural selection preserve a variant that appears so damaging in modern settings? A new study published in PLOS Genetics suggests a large part of the answer lies in the environment, showing that the biological consequences of APOE ε4 can shift dramatically depending on whether people live non-industrial or industrialized lifestyles.

The research, led by Marina M. Watowich and colleagues, took an unusually direct approach to this question. Rather than comparing separate studies conducted in different countries with different methods, the team worked with two Indigenous groups in which individuals of shared ancestry currently span a continuum of lifestyles, from traditional subsistence practices to urban, industrialized living. The first group was the Turkana of Kenya, pastoralists in East Africa whose communities range from mobile livestock-keeping camps to settled towns. The second was the Orang Asli of Peninsular Malaysia, whose populations likewise include people practicing forest-based subsistence and others living in urban environments. Because both genetic background and lifestyle vary within these groups, the researchers could test whether the same gene behaves differently across environments within a single population, a design that minimizes the confounding that plagues cross-population comparisons.

The team focused on three domains of biology in which APOE is known to play a role: cholesterol metabolism, immune function, and reproduction. APOE encodes a protein that shuttles lipids through the bloodstream and is deeply involved in how the body handles cholesterol. It also modulates inflammatory and immune responses, and previous work has hinted that it may influence fertility. Participants were genotyped for the three major APOE isoforms, ε2, ε3, and ε4, and the researchers measured total cholesterol, LDL cholesterol, HDL cholesterol, a panel of innate immune biomarkers, and reproductive traits including reproductive lifespan and the number of children born. Crucially, they then formally tested for genotype-by-environment interactions, asking whether the effect of carrying ε4 depended on the lifestyle a person was living.

The first finding was reassuring in its consistency: the established effects of APOE on lipid biology held across all lifestyles. Having more ε4 alleles was associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol, regardless of whether a person was a mobile Turkana herder, an Orang Asli villager, or an urban resident of either population. This matters because some researchers have proposed that traditional diets and high physical activity might simply erase the lipid effects of ε4. The new data do not support that strong version of the hypothesis. The allele’s influence on cholesterol appears to be a robust, intrinsic feature of its biology, one that persists even when people eat little saturated fat and walk long distances daily.

Where the environment did matter was in the immune system. The researchers found lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli, meaning that the relationship between carrying ε4 and levels of circulating immune markers changed depending on whether individuals lived non-industrial or industrialized lives. Intriguingly, this interaction was not observed in the Turkana, suggesting that even among non-industrial populations, the environmental modulation of APOE’s immune effects is not universal. The authors interpret this as evidence that local ecological conditions, such as pathogen exposure, diet, or other lifestyle factors that differ between the two groups and between subsistence and urban settings, can reshape how the allele expresses itself in immune biology. This kind of genotype-by-environment interaction provides a concrete mechanism by which the costs and benefits of a genetic variant can differ between the settings in which humans evolved and the settings most people inhabit today.

The reproductive findings were more nuanced and, in some ways, more sobering for advocates of the idea that ε4 is straightforwardly beneficial in traditional contexts. Across the combined samples, having more ε4 alleles was correlated with an extended reproductive lifespan, the span of years during which a person reproduces. Such an effect could, in principle, help explain how the allele persisted through natural selection despite its late-life costs: if ε4 carriers can reproduce over a longer window, the allele might pay an evolutionary dividend early enough in life to outweigh its disadvantages in old age. Previous studies in other populations, including forager-horticulturalist groups, have reported positive associations between ε4 and fertility, fueling this evolutionary argument.

However, the new study tempers that narrative considerably. The association between ε4 and extended reproductive lifespan was relatively weak, and it was not consistent across the two populations studied. Moreover, a longer reproductive lifespan did not translate into a measurable increase in reproductive output: ε4 carriers did not have more children. From an evolutionary standpoint, reproductive output is what selection ultimately acts upon, so a weak, population-inconsistent extension of reproductive lifespan that fails to produce more offspring provides only limited support for the idea that fertility benefits maintain ε4 in the human gene pool. The authors are explicit that ε4 is not universally beneficial in non-industrial contexts, a conclusion that pushes back against overly simple stories about the allele being a blessing in the wild and a curse in the city.

What the study does establish is that industrialized environments can modify the biology of APOE ε4. The immune findings in the Orang Asli demonstrate that lifestyle can change what a genotype does to the body, and the consistent lipid effects show that some consequences of the allele are more environmentally buffered than others. This layered picture fits a broader theme in modern human genetics: the effects of many variants are context-dependent, shaped by diet, activity, pathogen exposure, and other exposures that have changed radically since the advent of agriculture, cities, and industrial food systems. For APOE ε4 specifically, the implication is that the allele’s strong association with neurodegenerative and cardiometabolic disease in industrialized nations may be, in part, a mismatch phenomenon, an ancestral variant pushed into an environment that amplifies its harmful effects while stripping away whatever advantages it once offered.

The work also carries practical implications for medicine and public health. APOE genotyping is increasingly discussed as a tool for predicting Alzheimer’s risk and tailoring interventions, but this study is a reminder that risk estimates derived from industrialized cohorts may not transfer cleanly to people living different lifestyles, or to populations with different local ecologies. Understanding precisely which environmental factors modulate ε4’s effects on immunity and lipid biology, whether pathogen burden, physical activity, dietary composition, or something else entirely, could point toward interventions that recreate protective aspects of non-industrial conditions. At the same time, the inconsistency between the Turkana and Orang Asli results cautions against assuming that any single traditional lifestyle confers uniform protection.

Ultimately, the study reframes a familiar genetic villain as something more conditional. APOE ε4 is neither an unambiguous liability nor an ancestral gift; it is a variant whose consequences are negotiated between genome and environment, with cholesterol effects that persist across contexts, immune effects that bend with lifestyle in some populations but not others, and reproductive effects too weak and inconsistent to tell a clean evolutionary story. By working with the Turkana and Orang Asli across their own lifestyle transitions, the researchers have provided some of the most direct evidence yet that the biology of a single gene can diverge between industrialized and non-industrial worlds. As more populations undergo subsistence transitions, studies of this kind will be essential for understanding how the genomic legacies of our evolutionary past interact with the environments of the present, and for predicting who bears the greatest burden from variants like ε4 as the world urbanizes.

Subject of Research: Environment-dependent effects of APOE ε4 on cholesterol, immune, and reproductive traits in Turkana and Orang Asli populations

Article Title: Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments

Article References: Watowich, M. M., Petersen, R. M., Brassington, L., Arner, A. M., Rodenberg, G., Tan Boon Huat, T. B. T. A., Tam, K. L., Schellenberg, E., bin Mohd Sayed, I., John, E., Kahumbu, J. C., Muhoya, B., Gurven, M., Trumble, B. C., Njeru, S. N., Martins, D., Ayroles, J. F., Lim, Y. A. L., Venkataraman, V. V., … Lea, A. J. (2026). Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments. PLOS Genetics, 22(9), e1012285. https://doi.org/10.1371/journal.pgen.1012285

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012285

Keywords: APOE ε4, genotype-by-environment interaction, Turkana, Orang Asli, cholesterol, innate immunity, reproductive lifespan, evolutionary medicine, PLOS Genetics, lifestyle transition, Alzheimer's disease risk, human population genetics