For decades, doctors have been puzzled by why women develop Alzheimer's disease at nearly twice the rate of men.
There are estimated 7 million people in the US live with Alzheimer's disease This number is expected to reach almost 13 million by 2050. Most cases, or about 2 out of every 3, occur in women.
New research suggests that estrogen, the predominant female sex hormone, may play a critical role, especially during the perimenopausal transition to menopause, when hormone levels in the body naturally begin to decline.
Estrogen is believed to have many functions in the body. for example, improving cardiovascular health and maintaining bone density. Estrogen is very important for 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 early perimenopause, which typically occurs in women in their 40s, as a target for hormone replacement therapy to maintain estrogen levels and possibly protect some women from developing dementia decades later.
“This interest is driven primarily by decades of preclinical studies, animal models and basic science research showing that menopause is a turning point in the development of Alzheimer's pathology,” said Lisa Mosconi, director of the Alzheimer's Disease Prevention Program at Weill Cornell Medicine.
Mosconi leads new $50 million global women's health research initiative called CAREor Reducing the risk of Alzheimer's disease in women using endocrinology. The analysis of biomarkers from nearly 100 million women is expected to be the largest analysis of why women are at greater risk of Alzheimer's disease.
The link between estrogen and dementia has received renewed attention following The Food and Drug Administration recently rescinded its decades-long black box warning about hormone replacement therapy. a move that could lead to many more women in their 40s and 50s being prescribed the treatment.
Doctors say easing restrictions could reduce stigma around hormone therapy. The FDA's decision could also pave the way for broader research into whether hormone replacement therapy may provide additional benefits, including protection against dementia.
Decreased 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 that play an important role in sexual and reproductive development.
Most women reach menopause between the ages of 45 and 55, says Dr. Monica Christmas, a gynecologist and director of the menopause program at UChicago Medicine. The transition can begin several years earlier, during perimenopause, which usually begins when women are around 40 years old. This is when symptoms such as hot flashes, night sweats, mood changes and sleep disturbances often appear.
Menopause symptoms are thought to be 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 malfunction. The brain may interpret the body as too hot and tell it to start sweating to cool down, resulting in hot flash symptoms. Hormone therapy can replenish these levels and help the body regulate its temperature.
What role does estrogen play?
Receptors for this sex hormone are found throughout our brains, says Rachel Buckley, an assistant 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 located in the hippocampus, which is an area [in the brain] something that we know is very closely related to memory and learning.”
Estrogen also helps create and maintain healthy blood flow in the brain, she added, and can 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 becomes a turning point for 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 wearable patches, creams, and pills, and may include estrogen, progesterone, or both. If estrogen helps protect our brains, it would make sense to replace estrogen levels through hormone therapy, which could provide some benefit.
However, it turns out the answer is much more complex, experts say, as research into hormone replacement therapy is controversial and ongoing.
However, evidence suggests that the perimenopausal transition may represent a critical window of opportunity when treatment can help some patients prevent dementia, says Dr. Kellyanne Niotis, a preventive neurologist in Florida and faculty member at Weill Cornell Medicine.
“One of the core beliefs is that during this perimenopausal window, hormone levels fluctuate rapidly and you may experience a dramatic drop in hormone levels. [estrogen] which can be bad for the brain,” Niotis said.
“The idea is that using hormones at a stable or constant level helps even out these fluctuations.”
A large analysis by Mosconi and her team published in 2023 in the journal Frontiers in Aging Neuroscience. found that there may be a middle ground for starting HRT for helping women combat cognitive decline.
Her team analyzed more than 50 studies and found that people who used estrogen therapy in middle age or within 10 years of their last menstrual period had a significantly lower risk of developing dementia.
Conversely, when combination hormone therapy was started after age 65, there was an increased risk of dementia.
Another large-scale analysis of 50 studies presented this fall at the annual meeting of the American Neurological Association found that the risk of developing Alzheimer's disease was 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 study, conducted by researchers in India, also found that among women who waited until they were 65 or older to start therapy, the risk of Alzheimer's disease increased by 38%.
However, according to Christmas, many of the studies conducted to date have been observational in nature and do not directly prove cause-and-effect. More rigorous research, including large-scale trials, is needed, she said.
Prescribed hormone therapy also may not behave exactly the same as estrogen, which is naturally produced by the body, she added, and also requires further study.
Why the timing of hormone therapy starts matters
The theory behind the critical window for starting hormone replacement therapy may be related to estrogen receptors in the brain, Mosconi said. During the transition to menopause, the density of estrogen receptors on brain cells becomes increasingly higher. her research showed.
This is because as estrogen levels naturally decline, the brain increases the number of receptors available as a compensatory mechanism, trying to grab every drop of estrogen that is still available for use, she said.
But at some point, when estrogen levels become persistently 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's no point in putting estrogen back into the system because there's nothing for it to bind to,” Mosconi said.
Some unresolved questions remain, including how long women will have to stay on hormone replacement therapy or whether estrogen will be more protective for women with a genetic predisposition to Alzheimer's disease. It is also unclear whether the brain responds differently to estrogen produced by the body compared to hormone replacement therapy.
Men, on the other hand, have biologically different brains than women, Buckley says, because they have significantly fewer estrogen receptors and therefore less need for the hormone.
It's also unclear whether testosterone replacement therapy for men offers any potential benefit for preventing Alzheimer's disease, Niotis said. Although some research suggests a link between men with low testosterone and dementia, much more research is needed before any definitive conclusions can be drawn.
Experts say it is too early to recommend hormone replacement therapy to prevent Alzheimer's disease.
“We don't currently use hormone therapy to prevent Alzheimer's disease,” Mosconi said. “Clinical guidelines currently discourage the use of hormone therapy for the prevention of Alzheimer's disease alone.”
Instead, HRT should be prescribed primarily to treat moderate to severe menopausal symptoms that may affect quality of life, such as hot flashes, night sweats, sleep disturbances or mood changes.
Niotis said alleviating these symptoms may help improve cognitive function, since people who sleep better have better moods and tend to think more clearly.
However, she hopes future research may provide more definitive answers.
“We hope that by eliminating this black box warning, we will have more women who start treatment and are less afraid to use it, and more doctors who are less afraid to prescribe it,” Niotis said.
