The ages at which a person starts and stops menstruating could impact their risk of developing dementia later in life, according to the largest study of its kind.

The analysis included health information from 273,260 female participants in the United Kingdom Biobank, and the findings suggest that those who start their period younger and go through menopause older have healthier aging brains, relatively speaking.

Specifically, researchers at University College London found that people who menstruated for 34 to 37 years had a 28 percent decreased risk of dementia compared to those with a shorter 'reproductive span'.

This correlation seemed to depend both on when menstruation started and when it stopped, either naturally or from reproductive surgery.

In humans, estradiol is the most potent of the estrogen family of hormones. Its level ebbs and flows throughout life, peaking during reproductive years and declining with menopause.

The current study uses menstruation as a proxy for these hormone levels. Participants who started menstruating at age 15 or older showed a 12 percent increased risk of dementia. Meanwhile, those who experienced menopause after the age of 50 had a 24 percent decreased risk for dementia.

Hormone replacement therapy, which supplements estrogen after menopause, didn't seem to impact the results. The associations were also consistent among people who carried genetic risk factors for dementia and those who did not.

"Based on the results of this study, estrogen might have a protective role in women in the development of dementia," the team at UCL concludes.

If that turns out to be true, it could help explain why more than 60 percent of people who develop this neurocognitive disorder are female. In fact, apart from age, sex is the greatest predictor of developing dementia that scientists know of.

Nevertheless, the effect of sex hormones on female brain aging is poorly understood. To date, the vast majority of brain research has been conducted on male brains.

Only 2 percent of published neuroimaging studies even bother to mention hormonal factors and only 0.5 percent have dug further. More than half of such investigations found statistically significant associations between female sex steroids and changes in the brain.

For instance, in postmortem brains of women who died with Alzheimer's disease – the most common form of dementia – scientists have measured relatively low estrogen levels.

Follow-up animal studies have revealed that the mammal brain is highly sensitive to estrogens, especially in regions associated with learning and memory. Some results on rodents even suggest that estradiol can improve neural connections in the hippocampus and possibly reduce the accumulation of protein plaques associated with Alzheimer's.

Similar investigations with human brains, however, have turned up conflicting results.

In 2021, a study of 99 middle-aged women revealed that a longer reproductive span, indicating more years of estradiol exposure was associated with larger volumes of gray matter in the brain – a tissue that is reduced in volume in those with Alzheimer's.

In 2020, however, an analysis of 16,854 women found that greater sex‐hormone exposure in life was associated with more apparent signs of brain aging, not less.

To tease apart these mixed results, researchers at UCL conducted what they say is, to the best of their knowledge, the largest analysis to date. Their findings suggest that cumulative estrogen exposure in life is tightly linked to healthy brain aging.

One of their more concerning findings is that people who underwent reproductive surgery faced an 8 percent increased risk of dementia.

Thankfully, it seems that this risk can be significantly ameliorated if the surgery is done later in life (in a patient's 40s or 50s as opposed to their 20s or 30s).

The authors at UCL, however, point out that many of these surgeries are unnecessary and done too young. According to some estimates, about 90 percent of hysterectomy surgeries are performed due to benign conditions, and 54 percent of women in the United States undergoing hysterectomy removed both ovaries. More than a third of this group were under the age of 44.

"When women undergo surgery due to such benign conditions, they go through an abrupt decrease in estrogen exposure and accelerated changes in the nervous system in the perimenopausal period," explain researchers at UCL.

"[R]eproductive surgery should be considered as an increased risk for dementia in clinical practice."

The current analysis has produced some of the most robust observational results to date, but it can only reveal associations at a population level.

Far more research is needed to say how estrogen might directly impact brain aging and what we can do it about it. There's even a chance other sex hormones, like progesterone, are also playing an overlooked protective role.

While the current study did not show improved cognitive health outcomes among those who received hormone replacement therapy, some researchers in the past have theorized that it is the timing of these treatments that matter to brain health, not just whether or not they occur.

Far more research is needed to determine why females tend to develop dementia at such higher rates than males, and how that risk can be reduced.

If we are to truly understand cognitive decline, experts say prioritizing female brain studies in the future is a must.

The study was published in The American Journal of Geriatric Psychiatry.