Being female, early menopause, and hormone therapy were associated with an increased amount of regional tau in the brains of cognitively normal people who have elevated beta-amyloid, potentially putting them at a higher risk of developing Alzheimer's disease, according to a new  study published in JAMA Neurology, Judy George reports for MedPage Today.

Study details

For the study, researchers looked at PET scans from the Wisconsin Registry for Alzheimer's Prevention of 292 cognitively unimpaired adults. Of the scans, 193 were from women and 99 were from men, with an average age of 67.4 collected between November 2006 and May 2021.

Of the participants with elevated amyloid, the researchers found that being female, having menopause at an earlier age, and hormone therapy use were associated with higher amounts of tau proteins in the brain — which are used as an indicator of Alzheimer's disease.

They also found that starting hormone therapy more than five years after menopause onset was associated with higher amounts of tau proteins than those who started hormone therapy earlier

Discussion

According to Rachel Buckley from  Massachusetts General Hospital, who was a co-author on the study, many previous studies have looked at "the effects of menopause and hormone therapy on risk of dementia, [while] far fewer studies rigorously tested their association with Alzheimer's disease biomarkers, namely amyloid and tau, in clinically normal older women."

"Counterintuitively, we found that women with elevated amyloid who reported taking hormone therapy also showed higher tau burden," Buckley added. "One would have imagined taking hormone therapy might ameliorate the issues of lost estrogen because you are reintroducing estrogen into the body."

Instead, Buckley said, the research found that "higher risk was only associated with those women who had a long gap between their menopause onset and hormone therapy initiation — greater than 5 or 6 years."

The study's findings add to a growing body of literature suggesting menopause, and especially early or premature menopause, can contribute to a person's lifelong risk of developing Alzheimer's, according to Lisa Mosconi from  Weill Cornell Medicine, who was not involved in the study.

"This study also indicates that menopause hormone therapy may influence some aspects of Alzheimer's pathology, in keeping with previous evidence that women who take hormones during the menopause transition or soon after may experience greater brain-protective benefits as compared to those who start taking hormones later on in life," Mosconi said. "Overall, the connection between menopause and Alzheimer's disease has been overlooked for far too long, despite its potential significance."

Previous studies have suggested that hormone therapy could ameliorate cognitive impairment in women who were either menopausal or postmenopausal, the study noted. But 20 years ago, the Women's Health Initiative (WHI) study found that using hormone therapy was associated with roughly a two-fold higher incidence of probable dementia compared to a placebo.

"When it comes to hormone therapy, timing is everything," said JoAnn Manson, co-author of the new study and lead investigator on the WHI study. "Our previous findings from the WHI suggested that starting hormone therapy early in menopause, rather than late initiation, provides better outcomes for heart disease, cognitive function, and all-cause mortality — and this study suggests that the same is true for tau deposition." (George, MedPage Today, 4/3)