For decades, doctors have wondered why women develop Alzheimer’s disease almost twice as often as men.
There are an estimated 7 million people living with Alzheimer’s in the United States, and that number is expected to reach nearly 13 million by 2050. The majority of cases, approximately two in three, occur in women.
A host of recent research suggests that estrogen, the predominant female sex hormone, may play a key role, more specifically in the transition from perimenopause to menopause when the body’s hormone levels begin to naturally decline.
Estrogen is thought to play various roles in the body, such as improving cardiovascular health and maintaining bone density. Estrogen is very important for the brain and is considered a neuroprotectant, as it helps protect brain cells from inflammation, stress, and other forms of cellular damage.
Alzheimer’s researchers have focused on the early period of perimenopause, which typically occurs between ages 40 and 45, as a target for hormone replacement therapy to maintain estrogen levels and possibly protect some women against the possible development of dementia decades later.
“This interest primarily stems from decades of preclinical research, animal model studies and basic research showing that menopause is a turning point for Alzheimer’s pathology,” said Lisa Mosconi, director of the Alzheimer’s Prevention Program at Weill Cornell Medicine.
Mosconi led a new global women’s health research initiative, called CARE, with a budget of $50 million. After analyzing the biomarkers of almost 100 million women, it is expected to become the largest study into the reasons why they are at higher risk of Alzheimer’s disease.
The link between estrogen and dementia has returned to the spotlight after the Food and Drug Administration (FDA) recently lifted its decades-old warning on hormone replacement therapy, a move that could lead to many more women in their 40s and 50s being prescribed the treatment.
Doctors noted that easing restrictions could reduce the stigma around hormone therapy. The FDA’s action could also pave the way for broader research into whether hormone replacement therapy is capable of offering additional benefits, including dementia prevention.
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 present in women and, to a lesser extent, in men, and they play an important role in sexual and reproductive development.
Most women reach menopause between ages 45 and 55, according to Dr. Monica Christmas, a gynecologist and director of the menopause program at UChicago Medicine. The transition can begin years earlier, during perimenopause, which usually begins around age 45. This is when symptoms such as hot flashes, night sweats, mood swings and sleep disorders usually appear.
The symptoms of menopause are believed to be caused by decreased levels of estrogen and progesterone in the body. For example, when estrogen levels decrease, the body’s internal thermostat, controlled by the hypothalamus in the brain, begins to malfunction. The brain can interpret that the body is too hot and tells it to start sweating to cool down, causing symptoms of hot flashes. Hormone therapy can replenish those levels and help the body regulate its temperature.
What role does estrogen play?
Receptors for this sex hormone are found throughout the brain, according to 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,” he said. “It is located in the hippocampus, an area (of the brain) that we know is closely related to memory and learning.”
Estrogen also helps generate and maintain healthy blood flow in the brain, he added, and may even help the brain use energy more efficiently. However, during menopause, estrogen levels begin to decline, which can leave the brain more vulnerable to damage.
“Once the brain loses the protective effects of estrogen and other sex hormones, a turning point occurs in the accumulation of Alzheimer’s pathology in the brain,” Mosconi explained.
Can hormone replacement therapy fight dementia?
Hormone replacement therapy (HRT) is available in many forms, including patches, creams, and pills, and may include estrogen, progesterone, or both. If estrogen helps protect our brain, it would make sense that replacing levels through hormone therapy could confer some kind of benefit.
However, according to experts, the answer is much more complicated than that, as research on hormone replacement therapy is conflicting and still ongoing.
However, data suggest that the transition to perimenopause could represent a critical window of opportunity in which treatment could help some patients prevent dementia, added Dr. Kellyann Niotis, a preventive neurologist in Florida and a faculty member at Weill Cornell Medicine.
“One of the main beliefs is that, during this window of perimenopause, hormones fluctuate rapidly and a sharp decrease in estrogen can occur, which can be harmful to the brain,” Niotis said.
“The idea is that using hormones in a stable state or at a constant level helps balance those fluctuations,” Niotis added.
An extensive analysis conducted by Mosconi and his team in 2023 and published in Frontiers in Aging Neuroscience revealed that there may be an optimal time to start HRT to help women combat cognitive decline.
His team analyzed more than 50 studies and found that people who used estrogen therapy in middle age, or within 10 years after their last menstruation, had a significantly lower risk of dementia.
In contrast, when combined hormone therapy was started after age 65, the risk of dementia 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 was up to 32% lower among women who started HRT within five years of menopause than among those who received a placebo or no treatment. The article has not yet been peer reviewed or published in a journal.
The research, conducted by scientists based in India, also found that among women who waited until age 65 or older to start therapy, there was a 38% increase in the risk of Alzheimer’s.
However, many of the studies conducted to date have been observational, according to Christmas, and do not directly demonstrate a cause-and-effect relationship. More rigorous research, including large-scale trials, is needed, he added.
Prescription hormone therapy also may not behave exactly the same as the estrogen the body naturally produces, he added, and also requires more study.
Why is the timing of hormone therapy initiation important?
The theory that there is a critical time to start HRT may be related to estrogen receptors in the brain, Mosconi said. During the menopause transition, there is a progressive increase in the density of estrogen receptors in brain cells, their research has found.
This is because, as estrogen levels naturally decrease, the brain increases the number of receptors available as a compensatory mechanism to try to capture every little bit of estrogen that is still available for use, he explained.
But at some point, when estrogen is permanently low, the brain finally stops trying and gives up, and the estrogen receptors disappear, he added.
“That’s the end of the window of opportunity because once the estrogen receptors go away, there’s no point in putting estrogen back into the system because it has nothing to bind to,” Mosconi said.
Some questions remain unanswered, such as how long women would need to continue HRT or whether estrogen would be more protective for women with a genetic predisposition to Alzheimer’s. It is also unclear whether the brain responds differently to estrogen produced by the body compared to hormone replacement.
On the other hand, men have biologically different brains than women, Buckley said, as they have significantly fewer estrogen receptors and therefore need less of this hormone.
It is also unclear whether testosterone replacement therapy for men confers any potential benefits for Alzheimer’s prevention, Niotis said. While some studies have suggested an association between men with lower testosterone levels and dementia, much more research is needed before definitive conclusions can be reached.
Experts said it’s still too early to recommend HRT to prevent Alzheimer’s disease.
“At this time we do not use hormone therapy to prevent Alzheimer’s,” Mosconi explained. “Current clinical guidelines do not support the use of hormone therapy alone to prevent Alzheimer’s.”
Instead, HRT should be prescribed primarily to treat moderate to severe symptoms of menopause that can affect quality of life, such as hot flashes, night sweats, sleep disorders, or mood swings.
Niotis said that alleviating these symptoms can help improve cognition, since people who sleep better have better moods and tend to think more clearly.
Still, he is optimistic and believes that future research can provide more definitive answers.
“The hope is that with the FDA removing this warning, there will be more women starting therapies who are less afraid to use them, and more doctors who are less afraid to prescribe them,” Niotis said.
