A hormone best known for its role in reproduction may also help explain one of medicine’s mysteries: why women face a far higher risk of Alzheimer’s disease than men.
Researchers are investigating whether estrogen’s decline during menopause contributes to women’s higher Alzheimer’s risk, alongside age, genetics, and other factors.
Estrogen does far more than regulate the reproductive system. It also acts on the brain, where it helps neurons convert glucose into energy, supports memory and mood, and protects against inflammation and cellular stress. When estrogen levels fall during menopause, that protection fades.
What Happens to the Brain During Menopause
Menopause doesn’t happen all at once; the transition leading up to it, or perimenopause, is when the ovaries gradually begin making less estrogen. Menopause officially starts 12 months after a woman’s last period.
During this transition, hormone levels don’t taper off evenly. They can fluctuate wildly, leading some women to experience symptoms that can range from uncomfortable to unbearable—brain fog, weight gain, vaginal dryness, irritability, anxiety, mood swings, sleep problems, night sweats, and hot flashes.
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Estrogen helps regulate how the brain uses glucose for energy. Some imaging studies have found changes in brain glucose metabolism during the menopause transition, but researchers are still determining how those changes relate to cognitive symptoms and later brain health. When estrogen levels drop during menopause, the energy shortfall is thought to underlie many of menopause’s hallmark symptoms, from brain fog to temperature swings.
The Alzheimer’s Connection
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The brains of peri- and postmenopausal women began using glucose less efficiently.
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The perimenopausal and postmenopausal women had declines in estrogen-dependent memory tests compared to the men.
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The hippocampus shrank more quickly in postmenopausal women.
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Postmenopausal women had increased amyloid deposits compared with men.
The study did not determine whether the observed midlife changes would lead to Alzheimer’s disease.
Amyloid deposits are abnormal clumps of protein fragments that build up outside nerve cells, where they can damage connections between them and block chemical signals. While small amounts can be a normal part of aging, significant amounts of these deposits are a defining feature of Alzheimer’s disease.
“The reason why women are at greater risk for developing Alzheimer’s disease is not that they live longer, but because the disease can start earlier, during the midlife transition of the menopause,” Brinton told The Epoch Times.
Why the Brain ‘Switches Fuels’
Brinton’s research points to a specific mechanism: Estrogen loss triggers a sort of starvation response in the brain, forcing it to use alternate fuels, including fat-derived ketones and its own white matter, the tissue that insulates nerve fibers and speeds communication between brain cells.
While this may be fine in the short term, it isn’t a good long-term strategy, which is why the brain adapts and switches to an alternate fuel source, she said.
Estrogen therapy, also called hormone replacement therapy or HRT, can help prevent this fuel switch—but only if started near the onset of menopausal symptoms, Brinton said. HRT is a treatment that provides estrogen, and sometimes progesterone or progestin, to replace the natural hormones the body stops producing leading up to menopause.
Which hormones a woman receives depends on several factors, including whether she has a uterus, her menopausal stage, symptoms, and medical history.
“Estrogen sustains health. It sustains function—estrogenic function; it doesn’t reverse disease,” she said. “Particularly if given at the right time—at the time of menopausal symptoms—not 10 years, not 12 years, not 20 years after the brain has changed.”
This is why there is a substantial body of evidence, including her own, she said, that has been published in the last decade showing that menopausal hormone therapy reduces the risk of developing Alzheimer’s disease—as well as Parkinson’s, multiple sclerosis, and ALS.
Brinton interprets the emerging research as supporting a possible protective effect. However, studies of hormone therapy and dementia have produced conflicting results, and clinical guidelines do not recommend hormone therapy solely to prevent dementia. Its effects on other neurodegenerative diseases remain uncertain.
Estrogen’s Protective Effect, Even in Older Women
The study drew on two large, independent datasets: blood and cerebrospinal fluid samples from living patients, and autopsied brain tissue.
“We don’t currently have a way to sample the brain during life for individuals. It’s too invasive, but having this post-mortem assessment is really the closest look that we can get at the brain and some of the hallmarks of Alzheimer’s disease,” Dr. Jacob Shaw, study co-author and resident physician at Massachusetts General Hospital/McLean Hospital, told The Epoch Times. Together, the two datasets let researchers examine Alzheimer’s biomarkers from multiple angles.
The women who used estrogen-only hormone therapy had fewer tau tangles (abnormal clumps of misfolded tau protein that accumulate inside brain neurons) and amyloid plaques in their brains, and the blood and cerebrospinal fluid in the living patients suggested less amyloid buildup—all characteristics associated with Alzheimer’s disease.
Amyloid plaques and tau tangles are characteristics associated with Alzheimer’s disease. However, the women who used estrogen-only hormone therapy had fewer of both in their brains, and the blood and cerebrospinal fluid in the living patients suggested less amyloid buildup.
“We expected to find a potential positive effect of hormone therapy, and we did. But what was most surprising was that we saw similar results across two different cohorts,” Jennifer Bruno, study author and principal investigator at the Brain Research to Understand Neurodevelopmental Outcomes Lab at Stanford Medicine, told The Epoch Times.
She added that the women who used the estrogen-only hormone therapy had lower levels of Alzheimer’s related pathologies in the samples they tested.
What’s Still Unknown
Menopausal hormone therapy can be used to treat bothersome menopausal symptoms after an individual assessment. It is not currently recommended solely to prevent dementia, and women considering it should discuss its potential benefits and risks with their clinician.
Currently, estrogen-only hormone therapy is only prescribed to women who have had hysterectomies because of the risk of endometrial cancer.
The study authors said that while the findings help them better understand the relationship between estrogen-only hormone therapy and markers of dementia in the brain, more research is needed. Questions remain, particularly about when a woman begins hormone therapy and its effects, and which women may benefit most.
“I think the timing is very important. If we can nail that down, I think that would be a great next step,” Bruno said.
Shaw said he would like to know which women could benefit most from hormone therapy.
“Is it women who are at high risk for Alzheimer’s with genetic markers that predispose them, or is it healthy women with no family history of Alzheimer’s?” Shaw said. “As we build more literature, we can take a more personalized approach to understanding who this therapy might benefit.”
