Linking Alzheimer's Genetic Marker and Higher Female Fertility

The Apolipoprotein-ε4 (APOE-ε4) allele has been linked to an increased risk for several types of diseases in aging populations, particularly Alzheimer’s and cardiovascular disease. And yet, this genotype continues to be widespread in around 20% of the human population despite its unfavorable effects.

Researchers have learned that the APOE-ε4 gene is linked to higher fertility in women in their attempt to understand how this unfavorable allele is surviving natural selection.

In a new study published on August 9^th, 2023 in Science Advances, the authors collaborated with the Tsimane (Chi-mahn-eh) community in Bolivia, a forager-horticultural society, to examine the effects of the allele using an evolutionary anthropological perspective. The study is titled “Apolipoprotein-ε4 is associated with higher fecundity in a natural fertility population.”

Benjamin Trumble, the study’s lead author and an associate professor of evolutionary anthropology at Arizona State University's School of Human Evolution and Social Change and Center for Evolution and Medicine, traveled to the Tsimane’s home region in the Bolivian Amazon lowlands to conduct this research.

Trumble and the Tsimane Health and Life History Project, which are jointly co-directed by Trumble, Hillard Kaplan, Michael Gurven, and Jonathan Stieglitz, have a long-standing partnership with the Tsimane to gather demographic and biomedical data and assist in offering medical care. This partnership has been in place for more than 20 years.

Their hunter-farmer lifestyle is more analogous to human existence before the Industrial Revolution than modern cities, and with over 17,000 inhabitants dispersed across 90 communities, it provides a unique window into health and aging without modern influences.

What I do is I try to understand what human health was like prior to industrialization. For 99% of human history, we were hunter-gatherers. The world we are living in today is really weird. It is this built environment that we have created that is entirely different from what it was throughout most of human evolution. We are now essentially operating outside of the manufacturer's recommended warranty.

Benjamin Trumble, Study Lead Author and Associate Professor, Evolutionary Anthropology, Arizona State University

Trumble and the other researchers gathered information from 795 Tsimane women, whose ages ranged from 13 to 90, for this particular study. The study team not only obtained genetic information to identify the most common alleles for each person, but also details on their fertility, such as the age of their first birth, the interval between births, the total number of live births, etc.

In their analysis of the data, the researchers discovered that Tsimane women who carried one APOE-ε4 allele had .5 more births than those who did not. When two copies of the APOE-ε4 allele were present, the number of live births increased even higher, with these women having, on average, two more live births than women lacking this particular allele.

Trumble added, “What we found in this population was that women began reproducing almost a year earlier if they had the APOE-ε4 allele and they had shorter interbirth intervals. 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.”

Due to the benefits occurring in one’s early to mid-life years, which are passed on to their offspring, this advantageous effect on fertility could assist in clarifying why an allele that has such an adverse effect in one’s later life through the increased risk of developing Alzheimer’s or cardiovascular disease has not been weeded out by natural selection.

“Genes that are associated with diseases that occur after the age of reproduction, or after reproduction has already started, are in “selection’s shadow”. 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 have already had all your kids,” Trumble further stated.

Other, smaller studies have revealed other benefits of the APOE-ε4 gene, such as the fact that children in Brazil are more resilient to environmental infections and parasites, such as Giarada, than those who do not carry the allele, leading to superior cognitive functioning and faster development rates.

Trumble further noted, “If you spend a calorie on growth, you can't spend it on immune function and vice versa, so if you are sick all the time, you have to invest a lot of energy in immune function, and you can’t grow as fast. Children with the APOE-ε4 allele seem to have better immune function, so they spend less time sick and can grow faster.”

The predominant negative consequence of the APOE-ε4 allele remains the increased risk of Alzheimer’s and cardiovascular disease in later life, notwithstanding the advantages of the allele that have been revealed.

It is interesting that the Westernized world is where this allele’s unfavorable effects are most prevalent. For instance, research conducted by the sizable multidisciplinary team Trumble is a member of last year revealed that the Tsimane had the lowest incidence of dementia and Alzheimer’s in the whole world. This is true even though their community has the same 20% frequency of the APOE-ε4 allele.

What does this signify in terms of comprehending and addressing the adverse consequences of the allele in the most afflicted regions?

Trumble concluded, “We need to better understand global variation, and in particular, we need to kind of think outside the box and move beyond our focus on ‘this allele causes X disease’ and that's just how it is. Instead, we need to take a step back and say, what about in different environments? What about in the environments in which humans evolved?”

He further noted, “Because that actually opens up a whole other possibility for prevention or treatment by being able to mimic some of the aspects of that lifestyle. If we aren't seeing the same associations between APOE-ε4 and some outcome, then maybe if we kind of take a step back and we say, okay, what are the differences?”