For decades, doctors have wondered why women develop Alzheimer’s disease at nearly twice the rate of men.
An estimated 7 million people in the United States are living with Alzheimer’s disease, and that number is expected to rise to nearly 13 million by 2050. The majority of cases, about 2 in 3, occur in women.
New research suggests that estrogen, the predominant female sex hormone, may play a critical role, particularly in the perimenopausal transition to menopause, when the body’s hormone levels naturally begin to decline.
Estrogens are thought to perform a variety of functions in the body, such as improving cardiovascular health and maintaining bone density. Estrogen is very important to the brain and is considered neuroprotective, helping to protect brain cells from inflammation, stress, and other forms of cellular damage.
Alzheimer’s disease researchers are focusing on the early period of perimenopause, which typically occurs in the early to mid-40s, as a target for hormone replacement therapy aimed at maintaining estrogen levels and possibly protecting some women from developing dementia decades later.
“This interest comes primarily from decades of preclinical research, animal models and basic science showing that menopause is a critical point for Alzheimer’s pathology,” said Lisa Mosconi, director of the Alzheimer’s Disease Prevention Program at Weill Cornell Medicine.
Mosconi is leading a new $50 million global women’s health research initiative called CARE, or Reducing the Risk of Alzheimer’s Disease in Women Through Endocrinology. By examining biomarkers from nearly 100 million women, this will be the largest analysis of why women are at greater risk of developing Alzheimer’s disease.
The link between estrogen and dementia has gained attention after the Food and Drug Administration recently lifted the decades-old black box warning on hormone replacement therapy, a move that could lead to many more women in their 40s and 50s being prescribed treatment.
Doctors say easing restrictions could reduce the stigma surrounding hormone therapy. The FDA’s decision could also pave the way for broader research to determine whether hormone replacement therapy could provide additional benefits, including protection against dementia.
Decrease in reproductive hormones
Menopause occurs when the ovaries gradually produce less estrogen and progesterone, hormones that help regulate the menstrual cycle. Estrogen and progesterone are sex hormones found in women and, to a lesser extent, men, that play an important role in sexual and reproductive development.
Most women reach menopause between the ages of 45 and 55, said Dr. Monica Christmas, a gynecologist and director of the menopause program at UChicago Medicine. The transition can begin years earlier, during perimenopause, which typically begins when women are in their 40s. This is when symptoms such as hot flashes, night sweats, mood changes and trouble sleeping often appear.
Menopause symptoms are thought to be caused by a decrease in estrogen and progesterone levels in the body. For example, when estrogen levels drop, the body’s internal thermostat, controlled by the brain’s hypothalamus, begins to malfunction. The brain may interpret the body as being too hot and tell it to start sweating to cool down, leading to symptoms of hot flashes. Hormone therapy can replenish these levels and help the body regulate its temperature.
What role do estrogens play?
Receptors for this sex hormone are found throughout our brains, said Rachel Buckley, an associate professor of neurology at Massachusetts General Hospital whose research focuses on sex differences in Alzheimer’s disease.
“Estrogen is actually a very powerful hormone,” she said. “It is found in the hippocampus, an area [in the brain] which we know is very closely associated with memory and learning.
Estrogen also helps create and maintain healthy blood flow in the brain, she added, and may even help the brain use energy more efficiently. However, during menopause, estrogen levels begin to decline, potentially making the brain more vulnerable to damage.
“Once the brain loses the protective effects of estrogen and other sex hormones, that’s a turning point in the accumulation of Alzheimer’s pathology in the brain,” Mosconi said.
Can hormone replacement therapy fight dementia?
Hormone replacement therapy is available in many forms, including a wearable patch, cream, and pills, and may include estrogen, progesterone, or both. If estrogen helps protect our brains, it would make sense that replacing the levels with hormone treatment could confer some sort of benefit.
It turns out, however, that the answer is much more complicated than that, experts say, because research on hormone replacement therapy is mixed and ongoing.
However, data suggest that the transition to perimenopause may represent a critical window of opportunity where treatment could help some patients prevent dementia, said Dr. Kellyann Niotis, a preventative neurologist in Florida and faculty member at Weill Cornell Medicine.
“A common belief is that during this time of perimenopause, hormones fluctuate rapidly and you can have sharp drops in hormone levels. [estrogen] which can be harmful to the brain,” Niotis said.
“The idea is that using hormones at a steady state or constant level helps somehow even out these fluctuations.”
A large analysis by Mosconi and his team published in 2023 in Frontiers in Aging Neuroscience found that there may be a sweet spot for initiating HRT to help women combat cognitive decline.
Her team analyzed more than 50 studies and found that people using estrogen therapy in midlife, or within 10 years of their last menstrual period, had a significantly lower risk of dementia.
Conversely, when combined hormonal treatment was initiated after age 65, the risk of dementia was increased.
Another large-scale analysis of 50 studies presented this fall at the American Neurological Association annual meeting found that the risk of Alzheimer’s disease was up to 32 percent lower in women who started HRT within five years of menopause than in those who received a placebo or no treatment. The article has not yet been peer-reviewed or published in a journal.
The research, carried out by scientists based in India, also found that among women who waited until age 65 or older to start treatment, the risk of Alzheimer’s disease increased by 38%.
However, many studies done so far have been observational, Christmas said, and do not directly prove a cause-and-effect relationship. More rigorous research, including large-scale trials, is needed, she added.
Prescribed hormone therapy may also not behave exactly like estrogen produced naturally by the body, she added, and also requires further study.
Why Timing of Hormone Treatment Matters
The theory of a critical window for initiating hormone replacement therapy may be linked to estrogen receptors in the brain, Mosconi said. During the transition to menopause, the density of estrogen receptors on brain cells gradually increases, according to his research.
This is because as estrogen levels naturally decline, the brain increases the amount of receptors available as a compensatory mechanism to try to recover every small amount of estrogen still available for use, she explained.
But at some point, when estrogen levels are permanently low, the brain eventually stops trying and gives up, and the estrogen receptors disappear, she added.
“This is the end of the window of opportunity because once the estrogen receptors are gone, there is no point in reintroducing estrogen into the system because it no longer has anything to bind to,” Mosconi said.
Some questions remain, including how long women should take hormone replacement therapy or whether estrogen would be more protective for women with a genetic predisposition to Alzheimer’s disease. It’s also unclear whether the brain responds differently to estrogen produced by the body compared to hormone replacement.
Men, on the other hand, have biologically different brains than women, Buckley said, because they have far fewer estrogen receptors and therefore have a lower need for the hormone.
It’s also unclear whether testosterone replacement therapy in men confers any potential benefit for preventing Alzheimer’s disease, Niotis said. Although some studies have suggested an association between men with low testosterone and dementia, much more research is needed before definitive conclusions can be drawn.
Experts say it is still too early to recommend hormone replacement therapy to prevent Alzheimer’s disease.
“We don’t use hormone therapy for Alzheimer’s disease prevention at this time,” Mosconi said. “Current clinical guidelines do not endorse the use of hormone therapy solely for the prevention of Alzheimer’s disease.”
Instead, HRT should be prescribed primarily to treat moderate to severe menopausal symptoms that can affect quality of life, such as hot flashes, night sweats, trouble sleeping, or mood changes.
Niotis said relieving these symptoms could help improve cognition, because people who sleep better have better moods and tend to think more clearly.
Still, she remains optimistic that future research could provide more definitive answers.
“We hope that with the removal of this black box warning, more women will start therapies and be less afraid to use them, and more doctors will be less afraid to prescribe them,” Niotis said.
