Earlier age at menopause, later HT initiation linked to Alzheimer’s disease vulnerability

Key takeaways :

• Female sex, earlier menopause age and HT use were associated with higher regional tau positron emission tomography.
• These findings warrant trials assessing potential implications of HT timing on tau deposition.

Being younger at menopause onset and initiating hormone therapy after more than 5 years were both linked to increased tau vulnerability among women, according to a cross-sectional study published in JAMA Neurology.

“Early trials and observational studies suggest that use of exogenous hormones, via HT, may ameliorate cognitive impairment in menopausal or postmenopausal individuals,” Gillian T. Coughlan, MS, PhD, research fellow in the department of neurology at Massachusetts General Hospital at Harvard Medical School, and colleagues wrote. “Contrary to these findings, however, a seminal randomized clinical trial, the Women’s Health Initiative, found that HT use, particularly estrogen plus progestin, was associated with approximately twofold higher incidence of probable dementia relative to placebo.”

Researchers analyzed data from 292 cognitively unimpaired women and men (mean age, 67 years) who were enrolled in the Wisconsin Registry for Alzheimer’s Prevention between November 2006 and May 2021. Premature menopause at younger than 40 years, early menopause at age 40 to 45 years and regular menopause at older than 45 years, as well as current or past HT use and nonuse, were evaluated for associations.

The primary outcomes were seven tau positron emission tomography (PET) regions that show sex differences across the temporal, parietal and occipital lobes and the interaction of sex, age at menopause or HT and high beta-amyloid PET on regional tau. Secondary outcomes included the influence of HT timing in association with age at menopause onset on regional tau.

In the cohort, 66.1% were women, 52.2% of HT users were women and 19% of participants had abnormal beta-amyloid. Female sex (P < .001), earlier age at menopause onset (P < .001) and HT use (P = .008) were all associated with higher regional tau PET among individuals with elevated beta-amyloid compared with male sex, later age at menopause onset and HT nonuse, respectively, the researchers wrote.

Regions affected by HT use included medial and lateral regions of the temporal and occipital lobes. Later HT initiation at more than 5 years after menopause onset was associated with higher tau PET compared with early HT initiation (P = .001), according to the researchers.

“Female individuals who experience younger age at menopause may represent a subgroup for priority inclusion in Alzheimer’s disease prevention trials,” the researchers wrote. “Clinical trials to assess the potential implications of HT timing on tau deposition are also warranted.”