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One potential explanation is that the costs and benefits of APOE \u03b54 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 \u03b54, 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\u2014two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles\u2014we 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 \u03b54 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 \u03b54 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 \u03b54; however, we find that APOE \u03b54 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.<\/jats:p>","DOI":"10.1371\/journal.pgen.1012285","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:00:42Z","timestamp":1788890442000},"page":"e1012285","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4144-4225","authenticated-orcid":true,"given":"Marina M.","family":"Watowich","sequence":"first","affiliation":[{"name":"Vanderbilt University","place":["Nashville, Tennessee, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4530-7095","authenticated-orcid":true,"given":"Rachel M.","family":"Petersen","sequence":"additional","affiliation":[{"name":"Vanderbilt University","place":["Nashville, Tennessee, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9091-7714","authenticated-orcid":true,"given":"Layla","family":"Brassington","sequence":"additional","affiliation":[{"name":"Vanderbilt University","place":["Nashville, Tennessee, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8882-399X","authenticated-orcid":true,"given":"Audrey M.","family":"Arner","sequence":"additional","affiliation":[{"name":"Vanderbilt University","place":["Nashville, Tennessee, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Rodenberg","sequence":"additional","affiliation":[{"name":"Vanderbilt University","place":["Nashville, Tennessee, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan Bee Ting A\/P","family":"Tan Boon Huat","sequence":"additional","affiliation":[{"name":"Universiti Malaya","place":["Kuala Lumpur, Malaysia"],"department":["Department of Parasitology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kar Lye","family":"Tam","sequence":"additional","affiliation":[{"name":"Universiti Malaya","place":["Kuala Lumpur, Malaysia"],"department":["Department of Parasitology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Em","family":"Schellenberg","sequence":"additional","affiliation":[{"name":"University of Calgary","place":["Calgary, Alberta, Canada"],"department":["Department of Anthropology and Archaeology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0548-967X","authenticated-orcid":true,"given":"Izandis","family":"bin Mohd Sayed","sequence":"additional","affiliation":[{"name":"Hospital Orang Asli, Gombak","place":["Kuala Lumpur, Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Echwa","family":"John","sequence":"additional","affiliation":[{"name":"Turkana Health and Genomics Project, Centre for Community Driven Research - 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