Universidade Federal do Ceará
Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos

9 August 2023

The biggest known genetic risk factor for Alzheimer’s disease may boost fertility among women, a finding that could eventually help to develop new fertility treatments.

Every person inherits two copies of the apolipoprotein E (APOE) gene, which comes in three variants, or alleles: APOE2, APOE3 and APOE4. These encode for slightly different forms of a protein that helps to transport fats and cholesterol – which is important for making cells, hormones and vitamin D – around the body.

Studies have previously shown that people carrying an APOE4 allele have an increased risk of Alzheimer’s and heart disease, but these mainly focused on people living in the US or Europe. APOE4 increases the uptake of cholesterol from food compared with APOE3 or APOE2. Too high cholesterol levels can clog arteries, leading to heart disease. Research has also linked too much cholesterol in brain cells to slowed brain signalling, which may increase the risk of dementia.

“Despite the fact the allele has these negative impacts, it still occurs in between 15 to 25 per cent of the population across Europe and the US,” says Benjamin Trumble at Arizona State University. APOE4 may pass from generation to generation despite its negative effects because Alzheimer’s and heart disease generally occur later in life, when people tend to not reproduce, he says.

Alternatively, APOE4 may have benefits that have caused it to be retained as humans evolved, says Trumble. These benefits may be difficult to untangle in Western communities that have better access to modern amenities, such as birth control, he says.

Trumble and his colleagues therefore focused on the Tsimané, an Indigenous hunter-gatherer group in Bolivia. They analysed the genetics and fertility of 795 Tsimané girls and women, aged 13 to 90 years old, who lack access to birth control. No transgender people were included in the study. Fertility was assessed according to when the participants had children, how many they had and the time between them.

The team found that 80 per cent of the girls and women carried two copies of APOE3, while 18.5 per cent of them carried one copy of APOE4 and one copy of APOE3. The remaining 1.5 per cent of girls and women carried two copies of APOE4. None had any copies of APOE2.

By having the participants carry out surveys between 2002 to 2022, the team found that those with one copy of the APOE4 allele and one copy of APOE3 had 0.4 more children, on average, by around 47 years old compared with those who had two copies of APOE3. Those with two copies of the APOE4 allele had around 1.7 more children, compared with those who had two copies of APOE3, on average.

Participants with at least one copy of APOE4 gave birth again 10 per cent sooner after their previous birth, compared with those who had two copies of APOE3. There was also a roughly 10-month difference between when these participants gave birth to their first child, with those who had at least one copy of APOE4 doing so earlier.

In an environment where people can struggle to obtain enough food, so may have lower cholesterol, increased cholesterol uptake due to APOE4 could enhance fertility, says Trumble. This may explain why the allele was retained through evolution, he says.

By revealing new ways that APOE4 affects fertility, the findings could eventually lead to new fertility treatments, says Reinaldo Barreto Oriá at the Federal University of Ceará, Brazil.

Science Advances DOI: 10.1126/sciadv.ade9797