Against a backdrop of historical neglect and a future of political uncertainty, Science devoted a special issue to new research and perspectives on women’s health.
The collection, published Wednesday, highlights studies on the interplay between hormones, chromosomes and dementia, including findings with implications for men as well as women. It also features essays arguing for the importance of studying sex differences throughout biomedical research.
The issue comes when the word “women” in grants has been triggering special reviews at the NIH and the nation’s academic research is paralyzed by moves to slash funding or eliminate diversity mentions or both. But the problem is international in scope.
“Historically, and even to this day, biomedical research has overwhelmingly focused on only male and not female cells in animals in pre-clinical research, and females are also underrepresented in clinical trials,” Bronwyn Graham, a professor at the University of New South Wales in Sydney, said in a media briefing. “We know less about how to diagnose and treat health conditions in women as well as people with variations in sex characteristics, trans, and gender-diverse people.”
That means women are at greater risk for adverse reactions to drugs than men, they are more likely to die from undiagnosed stroke, and they receive less effective treatments for chronic pain conditions, said Graham, who is also director of the Centre for Sex and Gender Equity in Health and Medicine at The George Institute for Global Health. Her review’s first paragraph cites thalidomide, the morning sickness medication that was never adequately tested in women and caused limb deformities in their children.
Closer to our own time, Graham’s review also mentions lecanemab, the Alzheimer’s drug approved in 2023 and sold as Leqembi, which has delivered little or no benefit for slowing cognitive decline in women, a subgroup analysis indicated.
Alzheimer’s is the central focus of two research papers that examine menopause, hormone therapy, and the protein debris in women’s brains that presage dementia. Another paper, in mice, traces how genes on the inactive X chromosome in females boost cognitive ability later in life — and for male mice, too, if they’re genetically engineered to carry it.
Female sex is one of the strongest risk factors for developing Alzheimer’s disease and dementia. Two-thirds of people with Alzheimer’s disease are women, which can be attributed in part to women living longer than men, increasing their chances of acquiring the age-related disease.
Concern about hormone therapy harming cognition and raising the risk of dementia stems from the Women’s Health Initiative Memory Study, JoAnn Manson, principal investigator of the Boston site for the overall Women’s Health Initiative, told STAT. That study was famously halted in 2002 after women taking hormonal therapy during menopause showed an increased risk of developing breast cancer.
That 2003 memory study found a near doubling of dementia among women starting hormone therapy after age 65, Manson said, but in the Women’s Health Initiative, those who began hormone therapy at age 50 to 55 had no adverse effects on cognition. Results were similar in the 2015 Kronos Early Estrogen Prevention Study, also led by Manson in Boston.
“Key remaining questions are whether initiation of hormone therapy even earlier in the menopause transition, especially among women with bothersome hot flashes, night sweats, and disrupted sleep, can lead to improved cognition and a lower risk of Alzheimer’s disease compared to women not using hormone therapy,” Manson said.
The two Science stories zero in on those questions.
One study analyzed autopsy data from 268 women whose cognition was tested annually before they died, looking at the age when a woman entered menopause and her history of hormone therapy to see how they might relate to beta-amyloid and tau proteins, neurotoxins that can lead to Alzheimer’s and dementia.
Study author Madeline Wood Alexander, a Ph.D. student in the Rehabilitation Sciences Institute at the University of Toronto, noted how the timing of menopause in a woman’s midlife, usually around the age 50, corresponds with when Alzheimer’s pathology first develops in the brain. Previous studies have shown that vulnerability to Alzheimer’s-related changes in the brain increases in women from pre- to post-menopause.
The key player is estrogen and how it helps synapses do their job sending signals in the brain, she said. After menopause, estrogen falls unless hormone therapy restores it.
“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 said. “No research has yet investigated how menopause affects the links between synapses and Alzheimer’s disease.”
Her study has now found that women who reported taking hormone therapy after an early onset of menopause had less synapse-related vulnerability to tau tangles and cognitive decline compared to similar women not on hormone treatment. No significant association was found for beta-amyloid plaques, another sign of dementia.
“These findings highlight the importance of female-specific contributions to Alzheimer’s disease, and underscore the need for us to consider the role of hormones in understanding why women are at elevated risk,” Alexander said, emphasizing that the results show correlation, not cause and effect. “The menopause transition specifically might be an important key to help us unlock the biology of Alzheimer’s disease, and this is knowledge that will promote health for all brains.”
The other dementia study in Science looked at how menopausal hormone therapy might influence the risk of Alzheimer’s at varying ages. Women age 51 to 89 were divided into two groups: 73 who’d been on hormone treatment for an average of 14 years and 73 who hadn’t received hormone therapy. Their brains were monitored with PET scans for the growth of tau tangles over 3.5 years and for beta-amyloid deposits over 4.5 years.
The scientists found that women over 70 years old who were taking hormones had more tau accumulation in the brain. That wasn’t true for women in this age group who were not on hormone therapy: Their scans did not show the same increase in tau.
There was no significant difference between the two groups in how much beta-amyloid was found. Manson said there’s increasing evidence that greater vulnerability to tau rather than beta-amyloid accumulation in women may contribute to their higher Alzheimer’s risk. Whether early initiation of hormone therapy could lessen this excess risk warrants further study, she noted, given the looming burden of Alzheimer’s in years to come.
“The effect of menopausal hormone therapy on AD physiology seems to be somewhat specific to the tau protein,” study author Gillian Coughlan, an instructor in neurology at Massachusetts General Hospital, told reporters at the briefing. “These findings are consistent with current treatment guidelines around menopause and hormone therapy use.”
Current guidelines recommend that women use hormone therapy only if they’re within 10 years of their menopausal onset. This study’s results are generally consistent with findings from the Women’s Health Initiative trials, Coughlan said.
“These two papers add to the growing evidence that, for menopausal hormone therapy, timing is everything, and the ‘critical window hypothesis’ for estrogen applies not only to heart disease but also to cognition and Alzheimer’s disease,” said Manson, who is also chief of preventive medicine at Brigham and Women’s Hospital in Boston. “Whether early initiation of hormone therapy could help to mitigate this excess risk is an intriguing and pressing question.”
Justina Avila-Rieger, assistant professor of neuropsychology at Columbia University Vagelos College of Physicians and Surgeons, said the studies are valuable but that more information is needed on duration, dosage, and formulation of therapies, interactions with other reproductive history factors, and social/demographic factors.
“I think that to move forward we need to go beyond associations across groups and start asking more mechanistic questions,” she told STAT in an email. “Getting at the “why” (e.g., why do some women start spontaneous menopause earlier? What are the biological and social drivers?). Those types of questions will get us closer to understanding when and how to intervene.”
Avila-Rieger also called for more representative cohorts to identify strategies that protect the cognitive function of women from underrepresented groups, who are more likely than white women to experience cognitive decline and dementia. Also, women with high socioeconomic status are more likely to use hormone therapy, and physicians are more likely to recommend it to white women compared with Black and Latina women, she said.
On a more basic level, a study in mice also appearing in the Science special issue explored another change related to aging: the activation of genes in the “silent” X chromosome of female mice. When these genes were produced, they amplified the active X chromosome, ultimately improving memory and cognition in older female and male mice.
At least in aging mice, sex chromosomes contribute to longevity as well as better cognition, study author Dena Dubal, professor of aging and neurodegenerative disease at the University of California, San Francisco. Adding a second X chromosome to male mice improved their cognition while subtracting it from female mice worsened it.
“We were astounded to find that aging activated, or woke up, that silent X in the female brain in a brain region that’s very important to learning and memory,” she said. “The biological clock of the female brain ticks a little slower than that of men’s. If we can understand what makes women more resilient to typical brain aging, this reveals new pathways to targets for new medicines for women’s health, men’s health, and again, human health at large.”
The specific importance of research in women to their health and the general impact to be found for all people was a common theme among the scientists.
“We must stop equating women’s health with only reproductive health and fertility. Sex and gender impact the risk, symptom expression, and treatment response for all health conditions,” Graham said, citing neurological conditions, cardiovascular disease, and autoimmune disease. “At the end of the day, accounting for sex and gender in science and health care is not an ideology. It’s simply good science and best quality practice, and we all stand to benefit.”
STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.
