For decades, doctors have been puzzled by why women develop Alzheimer’s disease at nearly twice the rate of men.

There are an estimated 7 million people in the U.S. living with Alzheimer’s, with that number expected to reach nearly 13 million by 2050. A majority of cases, or about 2 out of every 3, are in women.

An emerging body of research is suggesting that estrogen, the predominant female sex hormone, may play a critical role, specifically in the perimenopausal transition to menopause, when the body’s hormone levels naturally begin to decline.

Estrogen is 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 shield brain cells from inflammation, stress and other forms of cellular damage.

Alzheimer’s researchers are focused on the early period of perimenopause, which typically occurs in a woman’s early- to mid-40s, as a target for hormone replacement therapy to maintain estrogen levels and possibly protect some women against developing dementia decades later.

“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 leading a new $50 million global women’s health research initiative called CARE, or Cutting women’s Alzheimer’s risk through endocrinology. Looking at biomarkers from nearly 100 million women, it’s expected to be the largest analysis of why women are at greater risk of Alzheimer’s disease.

The link between estrogen and dementia has gained renewed focus after the Food and Drug Administration recently lifted the decades-old black-box warning on hormone replacement therapy, a move that may lead to many more women in their 40s and 50s being prescribed treatment.

Doctors say loosened restrictions could reduce stigma around hormone therapy. The FDA’s move could also pave the way for broader research into whether hormone replacement therapy might offer additional benefits, including protection against dementia.

Declining 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 that are present in females and to a lesser extent in males 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 usually starts when women are in their mid-40s. That’s when symptoms such as hot flashes, night sweats, mood changes and sleep disturbances often appear.

It’s thought that menopause symptoms are caused by decreased levels of estrogen and progesterone in the body. For example, when estrogen levels drop, the body’s internal thermostat, controlled by the hypothalamus in the brain, begins to not work properly. The brain might interpret the body as too hot and tell it to start sweating to cool off, leading to 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 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 really powerful hormone,” she said. “It’s found in the hippocampus which is an area [in the brain] that we know is very closely associated with memory and learning.”

Estrogen also helps to build and maintain healthy blood flow in the brain, she added, and can even help the brain use energy more efficiently. During menopause, however, the levels of estrogen begin to decline, potentially leaving the brain more vulnerable to damage.

“Once the brain loses the protective effects of estrogen and other sex hormones, it’s a turning point for Alzheimer’s pathology accumulation in the brain,” said Mosconi.

Can hormone replacement therapy fight dementia?

Hormone replacement therapy is available in many forms, including a wearable patch, cream and pills, and can include either estrogen, progesterone, or both. If estrogen helps protect our brain, it would make sense that replacing levels through hormone therapy might confer some sort of benefit.

It turns out, however, the answer is much more complicated than that, experts say, as the research behind hormone replacement therapy is mixed and ongoing.

However, data suggests that the perimenopause transition might represent a critical window of opportunity where treatment could help some patients ward off dementia, said Dr. Kellyann Niotis, a preventive neurologist in Florida and faculty member at Weill Cornell Medicine.

“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,” said Niotis.

“The idea is that using hormones at a steady state or consistent level kind of helps even out those fluctuations.”

A large analysis from Mosconi and her team in 2023 published in Frontiers in Aging Neuroscience found that there may be a sweet spot for initiation of HRT for helping women fight cognitive decline.

Her team analyzed over 50 studies and found that people using estrogen therapy in midlife, or within 10 years of their final menstrual period, had a significantly lower risk of dementia.

Conversely, when combination hormone therapy was initiated after 65, there was an increased risk of dementia.

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 in those who received a placebo or no treatment. The paper is not yet peer-reviewed or published in a journal.

The research, which was done by scientists based in India, also found that among women who waited until they were 65 or older to start therapy, there was a 38% increase in Alzheimer’s risk.

However, many of the studies performed to date have been observational, said Christmas, and do not directly prove a cause and effect relationship. More rigorous research including large scale trials are needed, she added.

Hormone therapy that is prescribed may also not behave exactly like estrogen that is produced naturally by the body, she added, and also requires further study.

Why timing of hormone therapy matters

The theory of a critical window to initiate hormone replacement therapy may be related to estrogen receptors in the brain, said Mosconi. During the transition to menopause, there becomes a progressively higher density of estrogen receptors on brain cells, her research has found.

This is because, as estrogen levels naturally decline, the brain increases the amount of available receptors as a compensatory mechanism to try and grab every little bit of estrogen that’s still available to be used up, she said.

But at some point, when estrogen is permanently low, the brain ultimately stops trying and gives up, and the estrogen receptors disappear, she added.

“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,” said Mosconi.

Some outstanding questions remain, including how long women would need to stay on hormone replacement therapy or whether estrogen would be more protective for women with a genetic predisposition to Alzheimer’s. It’s also unclear if the brain responds differently to estrogen the body makes compared to hormone replacement.

Men, on the other hand, have biologically different brains than women, said Buckley, as they have significantly less estrogen receptors and thus have a lower requirement of the hormone.

It’s also unclear if testosterone replacement therapy for men confer any potential benefit for Alzheimer’s prevention, said Niotis. While some studies have suggested an association between men with lower testosterone and dementia, much more research is needed before any definitive conclusions can be made.

Experts say it’s still too early to recommend hormone replacement therapy to prevent Alzheimer’s disease.

“We do not use hormone therapy for Alzheimer’s prevention right now,” said Mosconi. “Clinical guidelines currently do not endorse using hormone therapy only for Alzheimer’s prevention.”

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, sleep disturbances or mood changes.

Niotis said relieving these symptoms may help improve cognition, as people who sleep better have improved mood and tend to think more clearly.

Still, she is optimistic that future research may bring more definitive answers.

“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,” said Niotis.