Two studies investigated hormonal factors that may influence Alzheimer's disease risk in women.
One study linked menopausal hormone therapy with increased tau buildup in older women's brains.
The other tied early menopause to reduced synaptic integrity and more tau tangle buildup.
Possible connections between menopause and menopausal hormone therapy and Alzheimer's disease risk were probed in two studies that aimed to elucidate why Alzheimer's disproportionately affects women.
The first showed that cognitively unimpaired women over 70 years old on menopausal hormone therapy had more tau accumulation in three regions of the temporal lobe compared with those not on hormone therapy. The relationship was not significant in women under 70 taking hormone therapy, according to researchers led by Gillian Coughlan, PhD, of Massachusetts General Hospital in Boston.
The second study found that early menopause onset corresponded with reduced synaptic integrity, more tau tangle buildup, and faster cognitive decline. Exploratory analyses by Kaitlin Casaletto, PhD, of the University of California San Francisco, and co-authors suggested these relationships were attenuated in women who took menopausal hormone therapy.
Both papers were published in Science Advances. Neither study reported significant findings about amyloid-beta.
"We did not see a similar combined effect of age at menopause and synapse functioning for the other Alzheimer's disease pathology we looked at, which was beta amyloid," said Madeline Wood Alexander, a PhD candidate at the University of Toronto and co-author of the paper about early menopause.
"These relationships were specific to tau," Alexander said in a press briefing. "However, when we looked at cognitive decline, similar to what we saw for tau, we observed that women who had earlier menopause showed an association of greater synaptic dysfunction with faster cognitive decline. And by contrast, women with later menopause did not show this association."
"We also looked at associations between menopausal hormone therapy and amyloid burden, and we did not find compelling evidence for associations here," Coughlan pointed out. "So this kind of effect -- of menopausal hormone therapy on Alzheimer's disease pathophysiology -- seems to be somewhat specific to the tau protein."
Coughlan and colleagues followed 146 women ages 51 to 89 from the Harvard Aging Brain Study who were clinically normal at baseline; half had used hormone therapy and half had not. The researchers used PET to scan participants over 4.5 years for amyloid-beta and 3.5 years for tau. Neuroimaging started approximately 14 years after women had started hormone therapy.
In women 70 and older, hormone therapy users had faster regional tau accumulation than non-users. Tau buildup was localized to the entorhinal cortex (β=0.20, P=0.014), the inferior temporal gyrus (β=0.19, P=0.011), and the fusiform gyrus (β=0.19, P=0.023), and was reflected in cognitive decline. In women under age 70, links between hormone therapy and tau were negligible.
The associations were in brain regions vulnerable to pre-clinical Alzheimer's disease, Coughlan noted. Tau was associated with a history of menopausal hormone therapy use in older but not younger women, which is generally consistent with findings from the Women's Health Initiative trials, she added.
The new findings also "are consistent with current treatment guidelines around menopausal hormone therapy use," Coughlan said. "Current guidelines recommend that women only use hormone therapy if they are within about 10 years of their menopause onset, and not later down the line."
Casaletto's team examined clinical and autopsy data from 268 Rush Memory and Aging Project participants who entered spontaneous menopause at an average of 49.2 years. The researchers focused on synaptic dysfunction, which has been shown to incite and exacerbate Alzheimer's progression.
"Studies have shown that vulnerability to Alzheimer's-related changes in the brain increase in women from pre- to post-menopause. And so, while menopause broadly might be an important factor that underpins Alzheimer's disease risk in women, earlier age at menopause specifically seems to raise women's risk," Alexander noted.
"A key feature in the menopause transition is a dramatic decline in estrogens. These are hormones that are known to be sex hormones but also have many important functions in the brain, including protecting the synapses," she said.
The findings reinforce that sex biology is an important part of personalized treatment approaches for people at risk for dementia, Alexander observed.
"We know Alzheimer's disease disproportionately affects women and in contrast, Parkinson's disease disproportionately affects men," Coughlan added.
But there's little understanding of "how sex biology, how hormones, how gender factors can explain these sex differences in disease prevalence," she continued. "And that's quite surprising because if we understood how biological differences influence ... disease prevalence, surely that would go a long way to informed treatment, prevention, and diagnosis."
Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow
Disclosures
The study led by Coughlan was supported by the National Institute on Aging and the Alzheimer's Association.
Researchers reported relationships with pharmaceutical companies and nonprofit groups.
The study led by Casaletto was supported by the Alzheimer Society of Canada Research Program, the CIHR Canada Graduate Scholarships Program, the Harquail Centre for Neuromodulation, the Dr. Sandra Black Centre for Brain Resilience & Recovery, CIHR grants, the Alzheimer Society of Canada Research Program, the Alzheimer's Association, the National Institute on Aging, New Vision Research, the American Academy of Neurology, the Association for Frontotemporal Lobar Degeneration, and the American Brain Foundation.
Researchers reported no competing interests.
Primary Source
Science Advances
Source Reference: Coughlan GT, et al "Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer's disease" Sci Adv 2025; DOI:10.1126/sciadv.adt1288.
Secondary Source
Science Advances
Source Reference: Alexander MW, et al "The interplay between age at menopause and synaptic integrity on Alzheimer's disease risk in women" Sci Adv 2025; DOI:10.1126/sciadv.adt0757.