The brain is directly influenced by hormone changes, and scientists suspect this could explain why women are generally more likely to develop Alzheimer's disease.
Women are more likely to experience steep changes to their estrogen levels at different life stages, and a new study adds to evidence that those fluctuations might have something to do with brain health later in life.
The research is published in the journal Neurology.
"Our results suggest that hormonal exposure across different periods of a woman's life may have cumulative effects also on the cerebrovascular health in later life," says neurobiologist Anna Marseglia, of the Karolinska Institutet in Sweden.
Marseglia and her colleagues found that women with longer reproductive periods – and those who used hormone replacement therapy in menopause – tended to have fewer signs of small blood vessel disease in their brains at age 70.
"The findings suggest that the brain's blood vessels may play an important role in the link between estrogen and brain aging," Marseglia adds.
The study draws on data from 352 healthy Swedish women from the Gothenburg H70 Birth Cohort Studies, all born in 1944.
Each woman had an MRI (magnetic resonance imaging) brain scan at age 70, and most went again for a follow-up at age 75. Only cisgender women were included in this study.
Using magnets and radio waves, MRIs create detailed three-dimensional images of structures inside the brain, like blood vessels, white matter, and the cerebral cortex.
The women also reported the span of their reproductive years (age at menopause or double-ovary removal, minus the age they had their first period), and whether they had ever taken oral contraceptives or menopausal hormone therapies.
These details are considered a proxy for lifetime estrogen exposure, though the study didn't actually directly measure hormone levels.
MRI markers of small vessel disease in the brain include bright spots known as white matter hyperintensities, lacunes (small cavities in the brain filled with cerebrospinal fluid), cerebral microbleeds, and perivascular spaces in the basal ganglia that are unusually large.
For each extra year a woman's reproductive period lasted, her odds of having two or more signs of small vessel disease at age 70 went down by about 8 percent. Later menopause (rather than an earlier first period) was the dominant driver of this association.
Women who used menopausal hormone therapies also tended to have fewer signs of small vessel disease, and better integrity in the microstructure of their white matter.
For women who carried the gene APOE-ε4, a variant that increases a person's risk of Alzheimer's, hormone therapy was associated with greater cortical thickness in brain regions vulnerable to Alzheimer's disease. But there was no association for women without the APOE-ε4 variant.
"Our findings suggest that longer endogenous estrogen exposure and a history of oral contraceptive or menopausal hormone therapy use may support cerebrovascular integrity, with potential benefits for women's brain health in late life," the authors write.
But as it's an observational study, these results can't tell us anything about cause and effect.
Many other factors – for example, other hormones which also fluctuate with menopause – may be contributing to the associations seen here. Plus, with a relatively small, single-country cohort, it's unclear whether these trends would apply to broader populations.
It's also worth noting that many of the associations disappeared when the bar for statistical significance (the probability of the result occurring due to chance) was raised.
A major review of prior studies found no strong evidence that menopausal hormone therapy impacts dementia risk, for better or worse.
"The results cannot therefore be used as a basis for recommending hormone therapy for preventive purposes," says Yale neuroscientist Giulia Lorenzon, the study's first author.
They do, however, provide a basis for further research.
"Given the lack of sex-specific prevention strategies for cognitive disorders, clarifying estrogen's long-term impact on brain and cognition remains an important clinical priority in the era of personalized medicine," the researchers conclude.
The research has been published in Neurology.
This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.