Alzheimer’s genetic risk affects women and men differently years before symptoms appear

Researchers at the Barcelonaβeta Brain Research Centre (BBRC) have found that genetic risk for Alzheimer’s disease may influence cognitive performance in different ways in women and men, even years before clinical symptoms develop. The study, published in Biology of Sex Differences, highlights the importance of considering biological sex differences to better understand the earliest stages of Alzheimer’s disease and developing tailored approaches to disease prevention.

Beyond APOE: understanding genetic risk as a whole

Alzheimer’s disease is not caused by a single gene, but by the combined effect of many genetic variants. Although the APOE gene, particularly the APOE-ε4 variant, is the best-known genetic risk factor, much remains unknown about how overall genetic risk affects the brain while people are still cognitively healthy.

To address this gap, the BBRC team followed 318 cognitively unimpaired adults from the ALFA+ cohort, a population enriched for genetic risk of Alzheimer’s disease part of the BBRC’s ALFA study suported by ”la Caixa” Foundation, over a three-year period. The study examined how different types of genetic risk, estimated using polygenic risk scores, both global and focused on specific biological pathways, were related to changes in cognitive functions such as memory, attention, executive functions, and visual processing. Importantly, the researchers also studied whether these relationships differed by sex and by the presence or absence of brain amyloid, one of the earliest biological hallmarks of Alzheimer’s disease. 

“One of our main goals was to understand how genetic risk starts to influence cognition long before symptoms appear, and whether these early effects differ between women and men,” explains Patricia Genius, first author of the study and PhD student at the  Molecular Epidemiology and Data science group.

Sex-specific patterns depending on amyloid status

The results show that Alzheimer’s genetic risk does not affect everyone in the same way. Its relationship with cognition depends both on sex and on whether amyloid accumulation is already present in the brain.

In women, higher genetic risk was associated with poorer memory and worse executive functioning, skills involved in planning, organizing, and maintaining attention. These effects were especially evident in women with amyloid-positive brains, where higher genetic risk was linked to a greater decline over time in episodic memory and executive functions.

In women without detectable amyloid, genetic risk was mainly associated with executive functioning and was driven by biological processes related to cell signaling, immune response, and other early disease mechanisms. This suggests that some genetic effects may appear before amyloid becomes detectable.

In men with amyloid positivity, the association between genetic risk and worsening attention was largely explained by cardiovascular risk factors and appeared to involve genes related to responses to external stimuli.

In men without amyloid, higher genetic risk was linked to poorer visual processing, independently of genetic risk, cardiovascular risk, and neurodegeneration. In this case, no single biological pathway clearly explained the association.

“Understanding how genetic risk interacts with sex, and other molecular factors is essential if we want to move towards truly personalized prevention strategies,” says Dr Natàlia Vilor-Tejedor, corresponding author of the study and leader of the Molecular Epidemiology and Data science group at BBRC and Utrecht University.

Hormones and cardiovascular health as key factors

The study also suggests that certain biological factors may influence how genetic risk translates into cognitive changes.

In women, the link between genetic risk and changes in memory and executive functions became weaker after accounting for reproductive lifespan as an indirect indicator of lifetime exposure to estrogens. This points to a complex interaction between genetics, hormonal history, and cognitive ageing.

In men, cardiovascular risk emerged as a particularly relevant factor, especially in those with amyloid accumulation, reinforcing the idea that brain health and heart health are closely connected.

"Our findings suggest that factors such as hormonal history in women and cardiovascular health in men modulate how genetic risk impacts cognition. This reinforces the need to integrate these aspects into early prevention strategies", explains Dr. Anna Brugulat, senior author of the study and postdoctoral researcher at the BBRC.

Reference article: Genius, P., Fernández-Bonet, A., Rodríguez-Fernández, B., Gallay, C., Gonzalez-Escalante, A., Sánchez-Benavides, G., López-Martos, D., Esteller, M., Navarro, A., Gispert, J. D., Brugulat-Serrat, A., Vilor-Tejedor, N., & ALFA study (2026). Sex-specific early cognitive changes are linked to global and pathway-specific genetic risk for Alzheimer's disease in at-risk individuals. Biology of sex differences, 10.1186/s13293-025-00800-w. Advance online publication. https://doi.org/10.1186/s13293-025-00800-w