APPLETON, Wis. — For decades, medical experts have grappled with a stark disparity: women develop Alzheimer's disease at nearly twice the rate of men. With an estimated 7 million Americans currently living with the condition — and projections reaching nearly 13 million by 2050 — about two out of every three cases affect women. Now, a growing wave of research is pointing to estrogen, the primary female sex hormone, as a potential key to prevention, particularly during the perimenopausal years when hormone levels begin to fluctuate and decline.
Scientists are increasingly focusing on hormone replacement therapy (HRT) as a possible shield against dementia, especially if started early in the transition to menopause. This renewed interest stems from preclinical studies, animal models, and basic science that identify menopause as a 'tipping point' for Alzheimer's pathology. 'This interest comes primarily from decades of pre-clinical research, animal models, and basic science research showing that menopause is a tipping point for Alzheimer’s pathology,' said Lisa Mosconi, director of the Alzheimer’s Prevention Program at Weill Cornell Medicine.
Mosconi is at the helm of a ambitious $50 million global initiative called CARE — Cutting women’s Alzheimer’s risk through endocrinology — which will analyze biomarkers from nearly 100 million women to uncover why they face heightened dementia risks. The project, announced recently, aims to provide the largest dataset yet on the topic, building on emerging evidence that maintaining estrogen levels during perimenopause, typically in a woman's early to mid-40s, could safeguard brain health for decades.
Estrogen's role extends far beyond reproductive functions; it's considered neuroprotective, helping to protect brain cells from inflammation, stress, and damage while supporting cardiovascular health and bone density. Receptors for the hormone are widespread in the brain, including the hippocampus, a region crucial for memory and learning. 'Estrogen is actually a really powerful hormone,' said Rachel Buckley, an associate professor of neurology at Massachusetts General Hospital, whose work examines sex differences in Alzheimer’s. 'It’s found in the hippocampus which is an area [in the brain] that we know is very closely associated with memory and learning.'
Buckley added that estrogen promotes healthy blood flow and efficient energy use in the brain. But as women enter perimenopause — the years leading up to menopause, which most reach between ages 45 and 55 — estrogen and progesterone levels drop, potentially leaving the brain more susceptible. Symptoms like hot flashes, night sweats, mood swings, and sleep issues often emerge during this phase, driven by hormonal shifts that disrupt the brain's hypothalamus, the body's thermostat regulator.
Hormone therapy, available as patches, creams, or pills containing estrogen, progesterone, or both, can replenish these levels and alleviate symptoms. Dr. Monica Christmas, a gynecologist and director of the menopause program at UChicago Medicine, explained that the transition can start in the mid-40s. 'Most women reach menopause between the ages of 45 and 55,' she said, noting that perimenopause brings the initial hormonal instability.
The potential brain benefits of HRT have gained fresh momentum following a recent Food and Drug Administration decision to lift a decades-old black-box warning on the therapy. This change, aimed at addressing outdated concerns from the 2002 Women's Health Initiative study, could reduce stigma and encourage more prescriptions for women in their 40s and 50s. Experts hope it will spur broader research into HRT's role beyond symptom relief, including dementia prevention.
Yet the evidence remains nuanced. While some studies suggest benefits, others highlight risks depending on timing. A 2023 analysis by Mosconi's team, published in Frontiers in Aging Neuroscience and reviewing over 50 studies, found that women starting estrogen therapy in midlife — within 10 years of their last menstrual period — had a significantly lower dementia risk. In contrast, initiating combination HRT after age 65 was linked to increased risk.
Another large-scale review of 50 studies, presented this fall at the American Neurological Association annual meeting by scientists in India, reported up to a 32% lower Alzheimer's risk for women beginning HRT within five years of menopause compared to those on placebo or no treatment. However, starting after age 65 correlated with a 38% higher risk. This paper awaits peer review and journal publication.
Dr. Kellyann Niotis, a preventive neurologist in Florida and faculty member at Weill Cornell Medicine, described perimenopause as a 'critical window' due to rapid hormone fluctuations. 'One leading belief is that during this perimenopausal window hormones are fluctuating rapidly and you can have steep declines in [estrogen] which can be harmful for the brain,' she said. Stabilizing levels with HRT, she added, might mitigate these ups and downs.
Mosconi's research delves into why timing is pivotal: during perimenopause, the brain ramps up estrogen receptors in a compensatory effort as natural levels fall. 'That is the end of the window of opportunity because once the estrogen receptors are gone, there’s no point putting estrogen back in the system because it has nothing to bind to,' she explained. Once menopause fully sets in and receptors diminish, reintroducing estrogen may offer little benefit.
Despite these insights, many studies are observational, limiting causal conclusions. Christmas emphasized the need for more rigorous, large-scale trials. 'However, many of the studies performed to date have been observational, and do not directly prove a cause and effect relationship,' she said. She also noted that synthetic HRT may not mimic the body's natural estrogen perfectly, warranting further investigation.
Questions linger about duration of therapy, genetic factors like APOE4 predisposition to Alzheimer's, and differences between natural and replacement hormones. For men, who have fewer estrogen receptors, the picture differs. Buckley pointed out that men's brains are biologically distinct, with lower estrogen needs. Niotis mentioned tentative links between low testosterone and dementia in men but stressed that research is preliminary. 'It’s also unclear if testosterone replacement therapy for men confer any potential benefit for Alzheimer’s prevention,' she said.
Currently, guidelines do not support HRT solely for Alzheimer's prevention. 'We do not use hormone therapy for Alzheimer’s prevention right now,' Mosconi stated. 'Clinical guidelines currently do not endorse using hormone therapy only for Alzheimer’s prevention.' Instead, it's recommended for managing severe menopausal symptoms that impair quality of life, such as intense hot flashes or sleep disruptions, which indirectly may bolster cognition by improving rest and mood.
Optimism persists amid the uncertainties. The FDA's policy shift could normalize HRT use, enabling more women to start earlier and facilitating robust studies. 'The hope is that with the removal of this black-box warning that we’ll have more women that are starting therapies and are less afraid of using them, and more doctors that are less afraid of prescribing them,' Niotis said. As the CARE initiative unfolds, it promises to illuminate paths forward, potentially reshaping how we approach women's brain health in midlife and beyond.
In Appleton and communities nationwide, where aging populations grapple with rising dementia rates, these developments offer a glimmer of proactive possibility. While experts urge caution and personalized medical advice, the convergence of endocrinology and neurology signals a transformative era in women's health research.