"We think that the loss of those hormones at menopause renders those neurons more vulnerable to age-related cellular decline and pathologies like Alzheimer's," said Karyn Frick, a neuroscientist and professor of psychological and brain sciences at the University of Wisconsin-Milwaukee.
While the idea sounds logical on its face, studies that have looked at hormone replacement therapy (HRT) for dementia prevention have had mixed results. There are early hints that restoring estrogen during early menopause may protect brain health, but ultimately, more gold-standard clinical trials are needed to know for sure, experts told Live Science.
Lab and animal studies buttress the idea that estrogen could protect brain health.
An estrogen molecule. The body's levels of estrogen fluctuate in perimenopause, and they then dramatically decline and level off during and after menopause. (Image credit: theasis via Getty Images)
Researchers think that estrogen may help prevent the formation of the abnormal proteins — including one called amyloid beta — that accumulate, disrupt communication between neurons and ultimately kill cells in Alzheimer's disease. Amyloid beta is produced when a larger protein is cut the "wrong" way by an enzyme, Frick explained. Estrogen promotes the "normal" cutting of this protein, thus reducing amyloid beta, studies in lab mice show.
The hormone may also support brain health indirectly by improving sleep quality.
Mixed results with estrogen-only HRT
HRT for menopause comes in two main forms: treatments that include only estrogen, and combined therapies with both estrogen and progesterone. The treatment has a complicated history.
That said, the Women's Health Initiative study found that estrogen-only HRT came with an increased risk of endometrial cancers, and later analyses have backed up this idea. That's why today, clinical guidelines recommend that women who have not gotten a hysterectomy take combined HRT, while estrogen-only options are reserved for those who have had their uterus removed. (The added progesterone counteracts estrogen's thickening effect on the uterine lining.)
Laboratory data suggest that estrogen may help prevent the formation and accumulation of abnormal proteins that are related to Alzheimer's. (Image credit: KATERYNA KON/SCIENCE PHOTO LIBRARY via Getty Images)
Estrogen-only HRT was also tied to better clinical outcomes: Treated women were less likely to be diagnosed with dementia, were less likely to show clinical and functional cognitive decline, and had better scores on memory tests, on average, compared with untreated women. These findings drew on two large, separate groups of older women, reporting data from 21,400 people in total, but they didn't include data on when each woman started HRT.
Although the Neurology study's findings are promising, they don't necessarily match the results of other studies of estrogen-only HRT and dementia. For example, a slightly larger observational study, published in 2023, found that estrogen-only HRT was associated with an increased dementia rate.
One big finding from the Women's Health Initiative study was that starting HRT — either estrogen-only or combined — after age 65 was associated with worse cognitive function and increased dementia risk, said Yuko Hara, director of aging and Alzheimer's prevention at the Alzheimer's Drug Discovery Foundation.
An observational study published in August in the journal Alzheimer's & Dementia found that starting HRT between ages 46 and 56 was linked to a reduced risk of dementia. That study did not differentiate between estrogen-only and combined treatment; it lumped all of the data together.
Patches (pictured) are one form of systemic HRT. They deliver hormones through the skin and into the bloodstream. (Image credit: SVPhilon via Getty Images)A 2024 meta-analysis of randomized controlled trials also found that HRT had a cognitive benefit for women with surgical menopause; that finding was tied mostly to estrogen-only therapies.
Who might benefit, if anyone?
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"This is a distinct clinical population because the procedure can cause an abrupt, early loss of estrogen, rather than the gradual hormonal decline that occurs with natural menopause," Hara said.
HRT is not currently prescribed to prevent dementia — it is prescribed to ease menopause symptoms, such as hot flashes, night sweats and sleep disturbances. To settle the science on HRT and the brain, what's really needed is a well-designed clinical trial that follows women from perimenopause to postmenopause, Bruno said. That would reveal the effects of HRT on brain health and dementia risk more reliably than the studies done so far.
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