Women are about twice as likely to get Alzheimer’s disease as men. But women who take estrogen as hormone therapy after menopause have fewer telltale neurological signs of Alzheimer’s disease after death than women who don’t, scientists report August 12 in Neurology.

Previous studies of menopausal hormone therapy have produced conflicting results. Some have suggested that estrogen could protect against dementia, while others show no benefit or even potential harm, especially when hormone therapy begins after age 65. A caveat is that many these studies have relied on measures of cognitive decline or blood tests, which are more ambiguous than analyzing the brain itself after death.

“We realized that the main gap in the literature is one that no one really has looked at — these gold standards of Alzheimer’s, which are these postmortem neurophysiological outcomes,” says Hadi Hosseini, a neuroscientist at Stanford University.

Hosseini and his team analyzed two datasets that included measures from more than 5,000 women, all over 50 years old. While these women were alive, they participated in cognitive testing for dementia and other clinical tests. After death, some women donated their brains for further testing. The team focused on a subset of about 7 percent of these women who used estrogen-only hormone therapy. Estrogen-only therapy is generally prescribed to women who have had hysterectomies because using estrogen alone with an intact uterus increases the risk of endometrial cancer. The researchers didn’t have quite enough data from women taking a combination of estrogen and progesterone to do the same analyses, even though women with intact uteruses take this combination to reduce the risk of uterine cancer.

When analyzing these brains, the researchers looked for three hallmark signs of Alzheimer’s disease: amyloid plaques, tau-related neurofibrillary tangles and neuritic plaques. These protein bundles can build up in the brain, either in or around neurons, and impair how neurons function and communicate. Unlike cognitive or blood tests, these three markers combine to form a reliable measure of whether someone had Alzheimer’s while they were alive.

The researchers found that women who had used estrogen-only hormone therapy had 35 percent lower odds of having severe Alzheimer’s markers on autopsy than nonusers. The researchers also found that those on hormone therapy had fewer signs of Alzheimer’s when they were alive — they had lower amyloid levels in blood and cerebrospinal fluid, as well as lower odds of memory loss or functional decline.

“This study adds an important piece to the evolving evidence on menopausal hormone therapy (MHT) and brain health,” says neurologist Gayatri Devi at the Zucker School of Medicine at Hofstra/Northwell Health in New York, who was not involved in the study.

Previous studies in nonhuman animals may help explain the mechanism underlying the findings, Hosseini says. “Estrogen may reduce the production of some of these harmful amyloids and then also may help with the clearance.” But he and his team were not looking at those processes in this study.

The researchers emphasize that the findings should not be taken as proof that hormone therapy prevents Alzheimer’s disease but rather should spur future clinical trials on the subject. Tracking biomarkers and cognition from the start of menopause onward would help to definitively show whether hormone therapy has a protective effect against Alzheimer’s. Studying women taking a combined estrogen-progestogen will also be a crucial next step, as that is the more common hormone therapy for perimenopause.

These findings highlight “the importance of estrogen for brain health and longevity,” says Jennifer Bruno, a developmental psychologist and neuroscientist at Stanford University. “Women can advocate for future trials to really understand the causality of this.”