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

@article{watowich2026divergent,
  title = {{Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments}},
  author = {Marina M. Watowich and Rachel M. Petersen and Layla Brassington and Audrey M. Arner and Grace Rodenberg and Tan Bee Ting A/P Tan Boon Huat and Kar Lye Tam and Em Schellenberg and Izandis bin Mohd Sayed and Echwa John and John C. Kahumbu and Benjamin Muhoya and Michael Gurven and Benjamin C. Trumble and Sospeter Ngoci Njeru and Dino Martins and Julien F. Ayroles and Yvonne A. L. Lim and Vivek V. Venkataraman and Ian J. Wallace and Thomas S. Kraft and Amanda J. Lea},
  journal = {PLOS Genetics},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pgen.1012285},
  url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012285},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments
AU  - Marina M. Watowich
AU  - Rachel M. Petersen
AU  - Layla Brassington
AU  - Audrey M. Arner
AU  - Grace Rodenberg
AU  - Tan Bee Ting A/P Tan Boon Huat
AU  - Kar Lye Tam
AU  - Em Schellenberg
AU  - Izandis bin Mohd Sayed
AU  - Echwa John
AU  - John C. Kahumbu
AU  - Benjamin Muhoya
AU  - Michael Gurven
AU  - Benjamin C. Trumble
AU  - Sospeter Ngoci Njeru
AU  - Dino Martins
AU  - Julien F. Ayroles
AU  - Yvonne A. L. Lim
AU  - Vivek V. Venkataraman
AU  - Ian J. Wallace
AU  - Thomas S. Kraft
AU  - Amanda J. Lea
PY  - 2026
DA  - 2026/09/08
JO  - PLOS Genetics
DO  - 10.1371/journal.pgen.1012285
UR  - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012285
AB  - The apolipoprotein ε4 (APOE ε4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE ε4—which is ancestral in humans—has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE ε4 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 ε4, 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 directly tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that having more APOE ε4 alleles is 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 having more APOE ε4 alleles is 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 ε4; however, we find that APOE ε4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits. Author summary: The apolipoprotein 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 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 levels. 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.
SN  - 1553-7404
ER  -