We analyze the relationship between the reproductive history and the preclinical stages of Alzheimer’s disease

Alzheimer’s disease disproportionately affects women (two out of every three diagnoses), prompting scientists to investigate the impact of factors specific to women on the disease, such as reproductive history. 

In fact, pregnancy causes profound hormonal, immune, and even brain changes, including modifications to the hippocampus, a key region of the brain for memory and one of the first to be affected by Alzheimer’s disease. Given this high physiological demand, pregnancy could influence ageing processes and help explain some of the differences between men and women in the development of the disease. 

In this context, the Barcelonaβeta Brain Research Centre (BBRC), a research centre of the Pasqual Maragall Foundation, has conducted a study that analyses the relationship between reproductive history and various early-stage biomarkers specific to Alzheimer’s disease in postmenopausal women over time. 

The work, published in the journal Neurology, was conducted using data from 254 female participants in the ALFA+ cohort, promoted by “la Caixa” Foundation, and constitutes one of the first studies to jointly investigate this relationship during the preclinical stages of the disease. This cohort follows volunteers with no cognitive impairment, most of whom are first-degree relatives of someone with Alzheimer’s disease. In other words, this population has a high prevalence of risk factors for the disease.

Unlike previous work, this research is not limited to analysing the relationship between reproductive history and cognitive evolution. It also includes crucial and essential biomarkers of Alzheimer’s disease, such as brain β-amyloid accumulation and hippocampal volume. On the one hand, β-amyloid is one of the characteristic proteins of the disease and may begin to accumulate in the brain decades before the onset of the initial symptoms. On the other hand, the decrease in hippocampal volume is one of the most widely used structural markers to assess its progression. For all these reasons, the preclinical stages provide a particularly valuable opportunity to investigate which factors or variables may influence the trajectory of biological processes associated with Alzheimer’s disease.

The research suggests that, only in women with high levels of brain β-amyloid accumulation, the number of births may be related to the evolution of certain brain markers over time. This association was not observed in participants without amyloid pathology.

“These results do not suggest that having children increases the risk of developing Alzheimer’s disease", explains Clara Gallay, a PhD student at BBRC and the first author of the study. “What we observe is that the number of births could influence how certain brain changes evolve when the pathology is already present, although much more research is needed to understand the mechanisms involved".

Taken together, these results suggest that reproductive history related to pregnancy could interact with certain brain changes occurring in the earliest stages of Alzheimer’s disease, which reinforces the importance of incorporating specific factors related to women in the research on the prevention and early detection of the disease.

“These results are preliminary and require confirmation in larger cohorts", explains Dr. Anna Brugulat, a postdoctoral researcher at the BBRC and corresponding author of the study. “To establish causality, we need more studies with a larger sample size, direct hormonal measurements and longer follow-up periods. This is only the first step, but we are convinced that a better understanding of the role of reproductive factors in the earlier stages of Alzheimer’s disease is essential for developing more personalised prevention strategies.”

A pioneering and promising line of research

The scientific importance of the study is significant. There are not many studies that have explored the relationship between the number of births and cognitive function, including biomarkers specific to Alzheimer’s disease; in fact, to the best of our knowledge, only two previous studies have addressed this issue from that perspective.

The study also represents the first publication of this line of research at the Barcelonaβeta Brain Research Centre (BBRC) and marks the start of a research programme aimed at gaining a better understanding of how female-specific reproductive history and other variables can influence brain processes during early stages of the disease. Theories include biological factors, such as hormonal changes accumulated during pregnancies, as well as social or lifestyle aspects related to parenting. 

Identifying the factors that influence women’s cognitive development is key to bridging the historical research gap in women’s brain health. Achieving this in the early stages of Alzheimer’s, when there is still an opportunity for intervention, will go a long way toward optimising early diagnosis and consolidating more accurate and personalised medicine in the future. 

Reference article: Gallay, C., Soldevila-Domenech, N., López-Martos, D., Sanchez-Benavides, G., Huguet, J., Suárez-Calvet, M., Gispert, J. D., Salvadó, G., Sundermann, E. E., Grau-Rivera, O., Brugulat-Serrat, A., & ALFA study. (2026). Effect of parity and β-amyloid on cognition and hippocampal volume in postmenopausal women. Neurology®, 107, e218153. https://doi.org/10.1212/WNL.0000000000218153