Timing of Menopause Could Influence a Woman’s Risk for Alzheimer’s

TUESDAY, April 4, 2023 (HealthDay News) -- Women are known to be at higher risk of developing Alzheimer’s disease than men, and now a new brain scan study suggests the timing of both menopause and hormone replacement therapy use may play a role in this increased risk.

“Female sex, earlier age-at-menopause and delayed use of hormone therapy were all associated with higher levels of tau in the brain,” said first study author Gillian Coughlan, a research fellow at Massachusetts General Hospital in Boston. Beta-amyloid plaques and tau tangles are hallmarks of Alzheimer's disease.

“This finding, if replicated, is clinically meaningful because higher levels of tau in the brain typically predict cognitive [mental] decline in the coming years,” Coughlan noted.

The study wasn’t designed to say how, or even if, early menopause or delayed hormone therapy after menopause caused higher tau levels in the brain, just that they seemed to travel together.

For the study, 193 women and 99 men underwent positron emission tomography (PET) scans to look at levels of beta-amyloid and tau in seven regions of the brain. None of the people in the study showed any signs of thinking declines.

Women in the study had higher levels of tau compared to men, especially when they also had elevated beta-amyloid levels.

Women aged 40 to 45 when they entered menopause had higher tau levels on their PET scan, suggesting that more prolonged exposure to estrogen throughout life might protect against Alzheimer’s disease.

During menopause, levels of the female sex hormone estrogen drop dramatically. Tau levels were highest in the regions of the brain that are close to its memory center and involved in the progression of Alzheimer’s disease, the study showed.

Early or premature menopause only occurs in up to 10% of women. “This proportion of the female population may need to be considered an at-risk group if the findings are replicated,” said Coughlan.

Women who started taking hormone therapy more than five years after menopause had higher levels of tau in the brain, the new study found.

Hormone replacement therapy fell from grace after the Women's Health Initiative study was stopped short in 2002 because hormone therapy was shown to increase the risk of strokes, and breast and ovarian cancer. But short-term use of hormone therapy is now deemed safe for some women who have severe menopausal symptoms, such as hot flashes and night sweats. Another arm of this landmark study found that hormone replacement therapy use increased the risk for dementia among women aged 65 and older, which is in line with the new study's findings.

Women who took hormone replacement therapy within five years of menopause onset didn't have higher tau levels. “Hormone replacement therapy may only pose a risk to long-term cognition if it is started several years after menopause onset,” Coughlan said.

Alzheimer's disease does run in some families and is largely driven by the presence of the APOE4 gene. “Whether or not the presence of this gene influences the association between menopause, hormone therapy and Alzheimer's disease is under investigation,” Coughlan added.

The findings need to be replicated in a larger group of women, added corresponding author Rachel Buckley. She is an assistant professor of neurology at Massachusetts General Hospital/Harvard Medical School, in Boston.

“Our data certainly support the findings of the Women’s Health Initiative that suggest giving hormone therapy to women after a long delay postmenopause might increase risk for Alzheimer’s disease,” Buckley said. “There is certainly a case to be made for hormone therapy helping symptoms in the shorter term, but women should certainly have a consultation with their doctor about whether their situation supports longer-term use.”

The study was published online April 3 in JAMA Neurology.

Experts stress that timing may be the key when it comes to use of hormone replacement therapy after menopause.

“The current study expands our understanding of the interplay between female sex, Alzheimer's disease and menopause, and how hormone therapies may contribute to these relationships,” said Dr. Kejal Kantarci, the director of the Women’s Health Research Center and the associate director of the Alzheimer’s Disease Research Center at the Mayo Clinic in Rochester, Minn.

Hormone replacement therapy’s influence on tau was limited to women who started hormone therapy five years after menopause.

“Hormone therapies started early during menopausal transition did not impact tau deposition and are considered safe,” Kantarci said.

Yuko Hara, director of prevention and aging at the Alzheimer’s Drug Discovery Foundation in New York City, agreed.

“The findings are consistent with the existing literature suggesting that starting hormone therapy many years after menopause may be harmful to cognitive health,” said Hara.

Still, it’s too early to draw any firm conclusions about how hormone replacement therapy after menopause affects risk for Alzheimer’s disease, she said. “For a more definitive answer, we need amyloid and tau PET imaging data from randomized controlled trials that test hormone therapy against placebo in women within a specific time window of menopause,” Hara added.

Such studies are ongoing, she said.

“The decision on whether or not to take hormone replacement therapy should be made with your health care provider to maximize benefits such as relief from menopausal symptoms while minimizing risks,” Hara said.

More information

The Alzheimer’s Drug Discovery Foundation recommends these seven steps to protect cognitive vitality.

SOURCES: Gillian Coughlan, PhD, research fellow, neurology, Massachusetts General Hospital, Boston; Rachel Buckley, PhD, assistant professor, neurology, Massachusetts General Hospital/Harvard Medical School, Boston; Kejal Kantarci, MD, director, Women’s Health Research Center, and associate director, Alzheimer’s Disease Research Center, Mayo Clinic, Rochester, Minn.; Yuko Hara, PhD, director, prevention and aging, Alzheimer's Drug Discovery Foundation, New York City; JAMA Neurology, April 3, 2023, online