What Drives Alzheimer's in Women?

Female sex, early age at menopause, and hormone therapy use each were associated with higher regional tau in cognitively normal people with elevated beta-amyloid, cross-sectional PET data showed.

The highest levels of tau were seen in hormone therapy users who had a delay of more than 5 years between menopause onset and the start of hormone therapy, reported Rachel Buckley, PhD, of the Massachusetts General Hospital in Boston, and co-authors in JAMA Neurology.

"While a fair amount of studies have focused on the effects of menopause and hormone therapy on risk of dementia, far fewer studies rigorously tested their association with Alzheimer's disease biomarkers, namely amyloid and tau, in clinically normal older women," Buckley said.

"This is critical to know given that it still remains unclear what might be the driving mechanism of the menopause transition, and any use of hormone replacement, on risk for dementia," she told MedPage Today.

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

"But this is where it got interesting: after further investigation into this group of women who reported taking hormone therapy, we 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," Buckley said. "It seems that introduction of exogenous estrogens after a long pause is not a great idea."

The findings add to an increasing body of literature indicating that menopause -- especially early or premature menopause -- is a contributor to women's greater lifelong risk of Alzheimer's disease, noted Lisa Mosconi, PhD, of Weill Cornell Medicine in New York City, who wasn't involved with 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 told MedPage Today. "Overall, the connection between menopause and Alzheimer's disease has been overlooked for far too long, despite its potential significance."

Premature menopause -- which can be either spontaneous or the result of surgical intervention before age 40 or 45, respectively -- occurs in 1% to 10% of women and has been associated with worse dementia outcomes.

Early studies had suggested that hormone therapy might ameliorate cognitive impairment in menopausal or postmenopausal women, Buckley and colleagues noted. However, 2 decades ago, the seminal Women's Health Initiative (WHI) study found that HT use was associated with approximately 2-fold higher incidence of probable dementia relative to placebo, possibly due to initiating hormone therapy many years after menopause onset.

"When it comes to hormone therapy, timing is everything," co-author JoAnn Manson, MD, DrPH, who also was a lead investigator on the WHI, said in a statement. "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."

Buckley and colleagues used data from the Wisconsin Registry for Alzheimer's Prevention (WRAP), assessing PET scans of 292 cognitively unimpaired adults (193 women and 99 men) to determine amyloid and tau levels in seven brain regions. Mean age was 67.4 at tau scan; 52 participants had abnormal amyloid-beta and 106 were APOE4 carriers. A total of 98 women were past or current hormone therapy users. Data were collected between November 2006 and May 2021. Age at menopause and use of hormone therapy were self-reported.

Among participants with elevated amyloid, female sex (standardized β=−0.41, P<0.001), earlier age at menopause (standardized β=−0.38, P<0.001), and hormone therapy use (standardized β=0.31, P=0.008) were associated with higher regional tau PET compared with male sex, later age at menopause, and nonuse of hormone therapy. Medial and lateral regions of the temporal and occipital lobes were affected.

Initiating hormone therapy more than 5 years after menopause onset was associated with higher tau PET compared with early hormone therapy (β=0.49, P=0.001). Overall findings remained after adjusting for years of education, APOE4, cardiovascular disease risk, menopause symptom severity, and menopause-related sleep problems.

The study had several limitations, Buckley and co-authors acknowledged. The researchers didn't know what precipitated premature menopause or why women chose to start hormone therapy; both factors may have influenced the findings. In addition, most people in the study were white.

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