Women with a Gene Variant Linked to Increased Alzheimer’s Risk May Have Improved Fertility

This research could potentially lead to the development of new fertility therapies for women who carry the most common genetic risk factor for Alzheimer’s disease.

The apolipoprotein E (APOE) gene is present in all humans in two copies and has three different forms, or alleles: APOE2, APOE3, and APOE4. These code for variants of a protein that aids in the distribution of lipids and cholesterol, both of which are required for the synthesis of cells, hormones, and vitamin D.

Previous research has linked the APOE4 allele to an elevated risk of Alzheimer’s disease and cardiovascular disease, however this has primarily been done on populations in the United States and Europe. When compared to APOE3 and APOE2, APOE4 promotes the absorption of cholesterol from meals. High amounts of cholesterol in the blood can cause artery blockage and eventually heart disease. Slower brain signalling due to high levels of cholesterol in brain cells has been related to an increased 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,” explains Benjamin Trumble of Arizona State University. He explains that since Alzheimer’s and heart disease tend to strike in old age, when people are less likely to procreate, APOE4 may be passed down through the generations despite the harm it does.

Trumble argues that APOE4 may have been advantageous for humans, leading to its retention throughout evolutionary history. He argues that in Western societies where people have easier access to conveniences like birth control, it may be more complicated to disentangle these advantages.

As a result, Trumble and his team zeroed attention on the Tsimané, a Bolivian Indigenous hunter-gatherer community. Without access to contraception, they studied the genetics and fertility of 795 Tsimané women and girls aged 13 to 90. There were no transgender participants. Participants’ fertility levels were determined by analysing when they had children, how many children they had, and how long it took for each child to be born.

Eighty percent of the female participants were found to have two copies of APOE3, while 18.5% had one copy of APOE4 and one of APOE3. Only 1.5% of females have one copy of APOE4 and 2.5% have two copies. None of them carried the APOE2 gene.

The researchers showed that people who carried out surveys between 2002 and 2022 had an average of 0.4 more children by the time they were 47 years old if they carried one copy of the APOE4 allele and one copy of the APOE3 allele than those who carried two copies of the APOE gene. On average, parents with two copies of the APOE4 allele had 1.7 more children than those with two copies of the APOE3 allele.

There was a 10% reduction in the time between births in participants who had at least one copy of APOE4 compared to those who had two copies of APOE3. Those with at least one copy of APOE4 also gave birth to their first kid about 10 months earlier than those without a copy of APOE4.

According to Trumble, greater cholesterol uptake owing to APOE4 could improve fertility in a society where people struggle to secure enough food and may have reduced cholesterol as a result. He suggests this may be the evolutionary explanation for the allele’s persistence.

Reinaldo Barreto Oriá of Brazil’s Federal University of Ceará thinks the discoveries could pave the path for new fertility treatments by illuminating hitherto unknown effects of APOE4.