Lifetime estrogen exposure associated with better cognitive performance in women

A new study published in the Journal of Alzheimer’s Disease suggests that women who experience greater lifetime exposure to estrogen may exhibit better cognitive performance and maintain larger brain volumes as they age. The research indicates that factors such as a later age of menopause, a higher number of live births, and the use of hormone replacement therapy are linked to indicators of better brain health. These findings add to a growing body of evidence attempting to explain the biological underpinnings of sex differences in neurodegenerative diseases.

Dementia represents a significant decline in mental function that interferes with daily life, with Alzheimer’s disease being the most prevalent form. It is a well-documented fact in epidemiology that women face a higher lifetime risk of developing dementia compared to men. Despite this known disparity, the scientific understanding of how sex and gender influence the risk of Alzheimer’s disease has historically lagged behind other medical fields, such as cardiovascular research.

Scientists have sought to determine if this increased risk is connected to reproductive and hormonal factors unique to women. Estrogen is known to have various effects on the brain, but previous studies investigating its relationship with dementia have produced conflicting results.

Some research has suggested that longer exposure to natural estrogen is protective, while other studies have found no association or even potential harm. To clarify these complex relationships, a research team led by Emer R. McGrath from the University of Galway and the Framingham Heart Study conducted a comprehensive investigation. They aimed to determine how specific reproductive milestones relate to brain structure and mental sharpness in a large community-based sample of healthy women.

The researchers utilized data from the Framingham Heart Study Offspring cohort. This is a long-term research project that has tracked the health of participants and their descendants since the early 1970s. For this specific investigation, the team focused on women who attended their seventh examination cycle, which took place between 1998 and 2001.

The primary analysis involved 1,329 women who underwent neurocognitive testing and 1,165 women who underwent magnetic resonance imaging (MRI) of the brain. The average age of these participants was approximately 60 years. It is important to note that all subjects were confirmed to be free of dementia and stroke at the time of these examinations.

The team collected extensive data on reproductive history. They recorded the age at which each participant began menstruation (menarche) and the age at which they entered menopause. They also documented the number of live births each woman had and whether they had ever used post-menopausal hormone replacement therapy. In addition to historical data, the researchers analyzed blood samples to measure the concurrent concentrations of hormones, specifically estradiol and estrone.

To assess brain function, the participants completed a battery of neuropsychological tests. These assessments measured various cognitive domains, including abstract reasoning, visual-spatial skills, verbal memory, and processing speed. The researchers used standardized scores to compare performance across the group.

For the structural assessment, the researchers used MRI scans to measure total cerebral brain volume. They also specifically measured the volume of the hippocampus. The hippocampus is a critical brain structure involved in learning and memory, and its shrinkage is often one of the earliest signs of Alzheimer’s disease. Additionally, the team calculated a composite score designed to reflect cortical atrophy in regions typically affected by Alzheimer’s disease.

Beyond the cross-sectional analysis of brain scans and tests, the study included a longitudinal component. The researchers followed a sub-group of 921 women for a median period of ten years to track the incidence of new dementia cases. This allowed them to see if the reproductive factors measured at the start of the study predicted who would eventually develop the condition.

The study revealed several associations between markers of estrogen exposure and cognitive ability. Women who reported using hormone replacement therapy performed better on tests of abstract reasoning compared to those who did not. Similarly, women who had higher levels of estradiol in their blood showed superior reasoning skills.

The age at which a woman’s reproductive life began also appeared to matter. Women who experienced their first menstrual cycle at age 14 or older tended to have lower scores in abstract reasoning compared to those who started menstruation between ages 12 and 13. This suggests that an earlier start to menstruation, and thus a potentially longer total duration of estrogen exposure, was linked to better cognitive outcomes.

Visual-spatial performance was another area where reproductive history showed an impact. Women who reached menopause at age 52 or older scored higher on visual organization tests than those who reached menopause at the average age of 50 or 51. The number of children a woman had was also a strong predictor in this domain. Women with one or more live births demonstrated better visual-spatial skills than women who had no live births.

When analyzing the MRI data, the researchers found that reproductive history correlated with physical brain structure. Women who experienced menopause at age 49 or younger had significantly smaller hippocampal volumes compared to those who reached menopause at age 50 or 51.

The number of live births was positively associated with total brain size. Women who had given birth to at least one child had greater total cerebral brain volume than those with no children. Those with three or more children showed even greater volume and less atrophy in regions susceptible to Alzheimer’s disease.

However, the study also produced some findings that appeared contradictory. While hormone replacement therapy was linked to better reasoning skills, its use was associated with smaller total brain volumes. A similar pattern was observed for women with higher levels of estrone in their blood. Upon further investigation, the researchers noted that this negative association between hormone therapy and brain volume was only evident in women who were aged 60 or older at the time of the scan.

The longitudinal analysis provided evidence regarding the long-term risk of dementia. During the ten-year follow-up period, 93 women were diagnosed with dementia. The statistical models showed that women who entered menopause at age 49 or younger faced a higher risk of developing the condition. Specifically, early menopause was associated with an 80 percent increase in dementia risk compared to women who reached menopause at the reference age of 50 to 51.

In contrast, the use of hormone replacement therapy appeared to offer a protective benefit against the development of clinical dementia. Women who had used these therapies had approximately a 47 percent lower risk of developing dementia compared to those who had never used them.

While the results provide evidence supporting the neuroprotective role of estrogen, there are still limitations to consider. Because the study is observational, it can identify associations but cannot definitively prove that estrogen exposure causes better brain health. The data regarding the age of menarche and menopause relied on self-reporting by the participants, which introduces the possibility of recall errors.

The measurement of hormone levels was restricted to a single point in time. This snapshot may not accurately reflect a woman’s cumulative hormone exposure over decades. Furthermore, the researchers lacked detailed information on the specific types, doses, and duration of hormone replacement therapy used by the participants. They also did not have precise data on when women started therapy relative to the onset of menopause.

This missing information regarding timing is significant. Some theories suggest a “critical window” hypothesis, where hormone therapy may be beneficial if started near the onset of menopause but potentially neutral or harmful if started years later. The conflicting findings regarding brain volume in older women observed in this study might relate to this timing issue.

The researchers also pointed out that they lacked data on pregnancy complications such as gestational diabetes or pre-eclampsia. These conditions can influence long-term vascular health and might interact with dementia risk.

Future research is needed to validate these findings in more diverse populations, as the current sample was primarily of European ancestry. Subsequent studies should aim to capture more granular data on the timing of hormone therapy initiation. Investigating the potential anti-inflammatory properties of estrogen in the human brain could also help explain the mechanisms behind these observed benefits.

The study, “The association between reproductive factors and neurocognitive and neuroimaging markers of brain aging,” was authored by Emer R. McGrath, Matthew R. Scott, Rachel F. Buckley, Claudia L. Satizabal, Amy E. Werry, Charles S. DeCarli, Saptaparni Ghosh, Ramachandran S. Vasan, Shalender Bhasin, Joanne M. Murabito, Alexa S. Beiser, and Sudha Seshadri.