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By Anna Skinner
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Women who used estrogen-only hormone therapy had lower odds of developing dementia and fewer signs of Alzheimer's disease, according to a new study from Stanford Medicine that is drawing fresh attention to a treatment whose use has steadily declined in the United States over the past two decades.
Published in Neurology on Wednesday, the study examined more than 21,000 women and found that those who used estrogen-only menopausal hormone therapy were less likely to develop dementia and showed reduced Alzheimer's-related pathology, including amyloid plaques and neurofibrillary tangles, compared with women who did not use the therapy. Researchers said the findings provide new insight into the relationship between estrogen and Alzheimer's disease, though they emphasized the observational study does not prove hormone therapy prevents dementia.
“Our study is unique in that we looked at all the standards of Alzheimer’s diagnosis, including the gold-standard outcome: Alzheimer’s-associated hallmarks in autopsied brains,” Hadi Hosseini, an associate professor of psychiatry and behavioral sciences who is the study’s co-lead author, said in a Stanford press release. “No one has previously looked at substantial numbers of postmortem Alzheimer’s disease outcomes.”
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The Stanford-led study analyzed data from two large Alzheimer's research databases: the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. Investigators examined clinical diagnoses, brain imaging and biomarker data collected during life, as well as autopsy findings.
The study included women age 50 and older who either reported using estrogen-only menopausal hormone therapy or reported no hormone therapy use. Among the participants whose brains were later examined after death, researchers evaluated the presence of hallmark Alzheimer's abnormalities such as amyloid plaques and tau tangles.
In the autopsy cohort, women who used estrogen-only hormone therapy had 35 percent lower odds of increased Alzheimer's disease pathology than nonusers. Across the broader analysis, hormone therapy users had 39 percent lower odds of receiving a clinical dementia diagnosis, along with lower odds of memory and functional decline. Researchers also found evidence of reduced amyloid burden in blood and cerebrospinal fluid biomarkers among users of hormone therapy.
“[Menopausal hormone therapy] appears to exert a modest but meaningful and statistically significant protective effect on the risk of developing Alzheimer’s pathology,” co-lead author of the study Jennifer Bruno, instructor in psychiatry and behavioral sciences, said in a press release shared by Stanford. “While this is by no means more powerful than such very well-known factors as age, possession of the genetic variant known as APOE4 or a history of hypertension, it’s nonetheless quite a consistent effect, spanning multiple Alzheimer’s-related outcomes.”
While the findings add to a growing body of research examining the relationship between hormone therapy and brain health, not all experts agree that the results demonstrate a protective effect against Alzheimer's disease.
“While the findings are intriguing, there are several important considerations. First, the study began following participants at an older age than when hormone therapy is typically initiated. The timing of hormone use may be important when considering its potential effects on brain health and Alzheimer’s risk,” Allison Aiello, James S. Jackson Healthy Longevity Professor of Epidemiology at Columbia University, told Newsweek. “Second, the study focused on estrogen use rather than estrogen combined with progesterone. This distinction is clinically important, as estrogen alone is generally not prescribed to women with an intact uterus because it can increase the risk of endometrial cancer.”
Aiello said the findings add to a growing body of research, but that she “would be cautious about interpreting them as evidence that women should take estrogen alone to prevent Alzheimer’s disease.”
Pauline Maki, a professor of psychiatry, psychology and obstetrics and gynecology at the University of Illinois Chicago, said the new findings are not surprising because they mirror a pattern researchers have seen for decades in observational studies of hormone therapy. Historically, many studies compared women who chose to take hormone therapy with women who did not.
However, Maki said those groups often differed in important ways before treatment even began. Women who used hormone therapy tended to have higher incomes, better access to health care, more health literacy and other advantages associated with better long-term health outcomes, creating what researchers call a "healthy user bias."
According to Maki, randomized clinical trials, which are considered the gold standard for determining cause and effect, have consistently failed to show cognitive or memory benefits from hormone therapy. She pointed to multiple randomized studies that found hormone treatment had no meaningful effect on memory, as well as research examining Alzheimer's disease biomarkers that likewise found no protective effect. Maki also noted that the Women's Health Initiative Memory Study found a doubled risk of all-cause dementia among older women taking a combination of estrogen and progestin, while estrogen-only therapy showed neither an increased nor decreased risk. Similar findings have emerged from large population-based studies in countries with universal health care systems, she said, where healthy user bias is less likely to influence who receives treatment.
While Maki cautioned against using the new study to guide decisions about hormone therapy, she emphasized that hormone treatment can still be valuable for managing menopause symptoms such as hot flashes and sleep disruption, which themselves can affect memory, attention and quality of life. She said women should not view hormone therapy as a strategy for preventing Alzheimer's disease. Instead, she pointed to evidence-based approaches that can reduce dementia risk, including maintaining cardiovascular health, eating a plant-rich diet, engaging in regular aerobic exercise, staying socially connected, avoiding smoking and excessive alcohol consumption, and preventing traumatic brain injuries.
"About 40 percent of dementia risk is within our control," Maki told Newsweek, citing lifestyle factors that have been linked to healthier brain aging.
Bruno told Newsweek that while the study's findings don't change current clinical recommendations, the results "certainly didn't show evidence someone should stop" estrogen therapy because of dementia concerns. She urged patients to use the therapy for what it's prescribed for and that taking care of menopause symptoms "has really great benefits for a woman's body and health."
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Why Estrogen Matters
Scientists have long sought to understand why women account for roughly two-thirds of Alzheimer's disease cases. One theory is that the sharp drop in estrogen levels that occurs during menopause may influence brain health and contribute to the increased risk.
Previous research on hormone therapy and dementia has produced mixed results. In particular, concerns stemming from the Women's Health Initiative in the early 2000s contributed to a sharp decline in hormone therapy use nationwide. The Stanford researchers noted that their investigation focused specifically on estrogen-only therapy and incorporated autopsy-confirmed Alzheimer's pathology, providing a different perspective than many earlier studies.
The researchers cautioned, however, that the results should not be interpreted as evidence that hormone therapy can prevent Alzheimer's disease. Because the study was observational, it cannot determine whether estrogen itself caused the lower risk or whether other factors may have contributed to the differences between the groups.
Hormone Therapy Use Remains Low
Despite growing evidence supporting hormone therapy for many menopausal women, its use remains near historic lows. A Mayo Clinic study published earlier this year found hormone therapy use among U.S. women declined from 4.4 percent in 2007 to 1.7 percent in 2023, even though major medical organizations consider it a safe and effective treatment for many women experiencing menopause symptoms.
The findings arrive as many experts argue that misconceptions about hormone therapy continue to influence treatment decisions. Mayo Clinic researchers reported that hormone therapy usage has continued declining despite evidence supporting its safety and effectiveness for many women when used appropriately. Even among women ages 50 to 59, a group often considered among the most likely to benefit from treatment, only about 3.5 percent were using hormone therapy in 2023.
According to the Mayo Clinic study, factors such as misinformation, patient concerns and limited menopause-specific training among some clinicians may help explain why therapy rates remain low despite increasing public discussion about menopause.
Researchers said more work is needed to determine whether estrogen plays a direct protective role in the brain and whether specific types, doses or timing of hormone therapy could influence Alzheimer's risk. For now, they say the study adds to a growing body of evidence suggesting the relationship between estrogen and cognitive health may be more complex than previously understood
What Happens Next
Both Bruno and Hosseini told Newsweek that they agreed that their study results call for more research. More work is needed to better understand the timing of hormone therapy and the type of regimen that might be associated with the lower risk.
Further studies may adopt a prospective approach, such as enrolling women before they enter menopause and following them through menopause.
Contact Newsweek editors for this story: Jason Lemon and Anthony Murray.
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