Women face a disproportionate burden of Alzheimer’s disease (AD) and dementia in later life. Nearly two-thirds of individuals with AD dementia are women. Some of this disparity may reflect differences in hormone exposure. Unfortunately, the relationship between menopausal hormone therapy (HRT) and cognitive health has been unclear. But three new studies help sharpen our view of how HRT, menopause timing, and brain health may intersect.
Hormone therapy use and tau accumulation
A recent paper in Science Advances investigated associations between menopausal HRT use and accumulation of tau protein in the brain (a hallmark of Alzheimer’s disease).
Scientists from Harvard Medical School studied 146 clinically normal women as part of the Harvard Aging Brain Study. The women were aged 51–89 years at baseline; half used HRT and half did not. They underwent PET (positron emission tomography) imaging to measure amyloid-β (Aβ) and tau accumulation. The follow-up period was approximately 4.5 years for Aβ and 3.5 years for tau.
Key findings:
- Among women over age 70, those who had used HRT showed faster accumulation of tau in key brain regions of the temporal lobe compared to non-users.
- Among women under age 70, there was no association between HRT use and tau accumulation.
- The study did not find significant differences in Aβ accumulation by HRT use.
- The study found an indirect effect of HRT on cognitive decline mediated via regional tau accumulation.
Apparently, timing matters: HRT use in older age (commonly over 70) may accelerate tau accumulation. This process is linked to the progression of Alzheimer’s pathology and cognitive decline. The study shows a potential biological mechanism (tau propagation) through which hormone therapy influences brain aging and women’s dementia risk.
The study also shows that HRT doesn’t universally protect the brain. It may even have adverse associations if women start it late. Consequently, the study supports the idea of a “window of opportunity” for hormone therapy concerning brain health. However, the study did not specify the type of HRT (e.g., conjugated estrogens versus bioidentical) or the route of administration (oral versus transdermal), which limits its findings.
Age at menopause, brain synapses and Alzheimer’s risk
Another article in Science Advances investigated how menopause timing and brain synaptic health relate to Alzheimer’s and cognitive decline.
The authors used data from 268 women who donated brain tissue after death to the Rush Memory and Aging Project. The researchers focused on defects in the synapses (connections between brain neurons), which have been shown to initiate Alzheimer’s progression. They also measured post-mortem AD neuropathology (including tau tangles and Aβ) and evaluated long-term cognitive functioning before death.
Key findings:
- Women who experienced earlier menopause (i.e., less lifetime exposure to ovarian hormones) showed stronger associations between reduced synaptic integrity and faster cognitive decline and greater tau burden. In other words, women with earlier menopause also had greater brain synaptic loss and AD pathology.
- Exploratory analyses indicated that women with early menopause who used HRT had a less detrimental effect.
This study reinforces the concept that menopause timing (i.e., the age when ovarian hormone production ends) may serve as a modifier of brain aging and Alzheimer’s risk. Earlier menopause may increase risk by making the brain more vulnerable to synaptic degeneration and tau propagation. The interaction with hormone therapy suggests that maintaining hormonal exposure (or substituting it) may buffer this vulnerability. However, this is not definitively proven.
Age at menopause, estradiol-based HRT route, and cognitive performance
A third study, published in Neurology, gives a large cohort‐based look at cognitive outcomes rather than brain imaging or pathology.
This cross-sectional observational study used baseline data from the Canadian Longitudinal Study on Aging. It included 7,251 post-menopausal women and examined three cognitive areas: episodic memory, prospective memory and executive function. The study evaluated age at menopause and the type of estradiol hormone therapy (oral vs transdermal).
Definitions
Episodic memory: The memory of everyday events, such as times, location, geography, associated emotions, and other contextual information.
Prospective memory: Remembering to perform a planned action, such as remembering to call a friend at a specific time or take a prescribed medication every night.
Executive function: Essential mental skills that allow people to plan, organize, and complete tasks to achieve goals, including working memory, flexible thinking, and self-control.
Key findings:
- Earlier age at menopause was significantly associated with lower scores across all three cognitive domains: episodic memory, prospective memory, and executive function.
- Earlier menopause had more of an effect on executive function in women with 4 or more children and those with the APOE ε4 allele, which is related to Alzheimer’s disease.
- Transdermal estradiol use was associated with higher episodic memory scores compared to no HRT. Oral estradiol was associated with higher prospective memory scores compared to no HRT. Neither route had a significant effect on executive functions.
This large cohort study underscores that earlier menopause (i.e., shorter estrogen exposure) is associated with modest but consistent decreases in cognitive performance later in life. It also suggests that the type of HRT matters: different forms (transdermal vs oral) may support different cognitive domains. While this is observational and cannot prove cause and effect, it points to where further clinical trials could focus.
“Poor episodic memory can be a predictor for later-life Alzheimer’s disease, the most common form of dementia. Alzheimer’s disease risk is higher in older women and could be related to menopausal loss of neuroprotective sex steroids, including estradiol, the most potent estrogen.”
— Eef Hogervorst, PhD, Loughborough University
Study limitations
It’s worth emphasizing the important limitations of these studies:
- All three studies are observational, not randomized clinical trials. They don’t establish cause and effect; they only show associations between HRT and brain outcomes.
- Confounding is a major concern: women who choose or are prescribed HRT may differ in important ways from non-users. For example, Dr. Hogervorst, the lead author of the Neurology study, notes “Earlier loss of sex hormones (due to early menopause), as well as whether women take replacement sex hormones (HRT or MHT) are associated with socioeconomic factors and lifelong health, also affecting dementia risk which may lead to systematic bias in this type of research.”
- HRT formulations, doses, duration, and timing vary widely; many studies do not capture all of these in detail, limiting generalizability.
- Findings may not generalize across all racial/ethnic or socio-economic groups.
What do these studies mean for brain health, menopause, and hormone therapy?
These three recent studies advance our understanding of how menopausal hormone exposure, HRT timing, and brain pathology converge in women’s cognitive aging. They emphasize that when (age at menopause, timing of HRT) and what (route/form of HRT) matter. The studies show that HRT is not one-size-fits‐all when it comes to brain health. They also set the stage for more detailed studies to further clarify these findings:
- Timing matters: Both age at menopause and age of starting HRT appear to be important to brain health outcomes.
- Type of HRT matters: Transdermal and oral estradiol HRT may differentially impact episodic memory vs prospective memory.
- Measures matter: Tau accumulation may be affected more by the age of starting HRT than by amyloid beta. Transdermal vs. oral estradiol HRT may be related to different memory measurements.
While more research is needed, women who are considering HRT for brain health should talk with their doctors about their risk profile, history, age at menopause, age when starting HRT, and the type of HRT. Reducing Alzheimer’s risk in women will require multidisciplinary, life-course approaches — of which HRT may be one informed option, in the right context. Other efforts to preserve brain health are also important for preventing Alzheimer’s disease and dementia. They include physical activity, diet, and hearing/vision aids.
See our page on Hormones for Menopause and other news articles on dementia and Alzheimer’s disease.
