TEMPE, Ariz. – A genetic mutation associated with a heightened risk of diseases, including Alzheimer’s and cardiovascular disease, apparently does more than meets the eye. The mutation is found in 20 percent of all human populations, and researchers at Arizona State University were curious why the mutation survives the natural selection process, despite its negative effects later in life. They uncovered the surprising answer — Apolipoprotein-ε4 (APOE-ε4) allele appears to have a link to, among other things, increased fertility in women.
The researchers collaborated with the Tsimane (Chi-mahn-eh) community in Bolivia, a forager-horticultural society, to explore the APOE-ε4’s effects through an evolutionary anthropological lens. The Tsimane Health and Life History Project has cultivated a two-decade relationship with the Tsimane to gather demographic and biomedical data and provide medical care. Spanning 90 villages with over 17,000 inhabitants, the Tsimane’s lifestyle offers a unique insight into health and aging, devoid of modern urban influences.
“I try to understand what human health was like prior to industrialization,” explains study lead author Benjamin Trumble in a university release. “For 99% of human history, we were hunter-gatherers. The world we’re living in today is really weird. It’s this built environment that we’ve created that’s entirely different from what it was throughout most of human evolution. We are now essentially operating outside of the manufacturer’s recommended warranty.”
For this study, Trumble and the researchers gathered data from 795 Tsimane women, spanning 13 to 90 years-old. Genetic data was collected to assess the genetic variant’s prevalence in each individual, alongside fertility information, including the age of first birth, interbirth intervals, and total live births.
Upon analyzing the data, the researchers found that Tsimane women possessing one APOE-ε4 allele experienced an increase of 0.5 births, compared to those without it. For women with two copies of the APOE-ε4 allele, the average number of live births increased by two compared to those lacking this specific allele.
“Women began reproducing almost a year earlier if they had the APOE-ε4 allele and they had shorter interbirth intervals,” Trumble says. “Those two things combined allow them to have about half an additional kid if they have one copy or two additional kids if they have two copies.”
This unexpected boost in fertility might explain why a mutation with detrimental impacts later in life, such as increasing the risk of Alzheimer’s or cardiovascular disease, persists within the population.
“Genes that are associated with diseases that occur after the age of reproduction, or after reproduction has already started, are in ‘selection’s shadow,'” Trumble explains. “There have been a lot of arguments about the APOE-ε4 allele, that it may be an example of selection’s shadow, that you don’t develop Alzheimer’s until after you’ve already had all your kids.”
Additional studies have highlighted other advantages of the APOE-ε4 allele, such as improved handling of environmental pathogens and parasites, resulting in enhanced cognitive function and growth rates in children.
Despite these beneficial aspects, the allele’s negative impacts on Alzheimer’s and cardiovascular disease risk in later life remain substantial. Interestingly, the allele’s detrimental effects are most pronounced in Westernized nations. The Tsimane, possessing the same 20-percent prevalence of the APOE-ε4 allele, have the lowest rates of dementia and Alzheimer’s globally.
Trumble suggests that these findings could inspire novel approaches to understanding and mitigating the mutation’s adverse effects.
The study is published in the journal Science Advances.