Boston—Hormone therapy (HT) appears to be a factor in the deposition of tau pathology, which is associated with the development of Alzheimer’s disease.

That is according to a new cross-sectional study in the Journal of the American Medical Association Neurology that found female sex and earlier age at menopause were significantly associated with higher regional tau in the context of high beta-amyloid, as measured on the positron emission tomography (PET) signal.

The Massachusetts General Hospital researchers added, “Late initiation of HT following menopause onset may underpin the association between HT use and the elevated tau positron emission tomography signal.”

That could help explain sex differences in Alzheimer’s disease, according to the authors. “Postmenopausal females represent around 70% of all individuals with Alzheimer disease,” they explained. “Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high beta-amyloid. The biological mechanisms associated with higher tau deposition in female individuals remain elusive.”

The findings are contradictory in some ways to earlier research on the topic.

The cross-sectional study, which was conducted between November 2006 and May 2021, included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Analysis included cognitively unimpaired men and women with at least one F-MK-6240 and C-Pittsburgh compound B PET scan.

For the study, premature menopause was defined as occurring in those aged younger than 40 years, early menopause aged 40 to 45 years, and regular menopause aged older than 45 years. The researchers also focused on hormone therapy use, either current or past, and no use of HT.

The group of 292 cognitively unimpaired individuals included 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal beta-amyloid, and 106 (36.3%) were APOEε4 carriers. Slightly more than one-half (52.2%) of the females were past or current HT users.

The results indicated that female sex (standardized beta = –0.41; 95% CI, –0.97 to –0.32, P <.001), earlier age at menopause (standardized beta = –0.38; 95% CI, –0.14 to –0.09, P <.001), and HT use (standardized beta = 0.31; 95% CI, 0.40-1.20, P = .008) were linked with higher regional tau PET in individuals with elevated beta-amyloid compared with male sex, later age at menopause, and HT nonuse.

The researchers pointed out that affected regions included medial and lateral regions of the temporal and occipital lobes. They added that late initiation of HT (>5 years following age at menopause) was more predictive of higher tau PET compared with early initiation (beta = 0.49; 95% CI, 0.27-0.43; P = .001).

“In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated beta-amyloid. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical beta-amyloid elevated,” the authors concluded. “These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.”

Background information in the article pointed out, “In the context of high beta-amyloid, substantial evidence suggests that female individuals exhibit greater Alzheimer’s disease–related neurofibrillary tau tangles than males. What remains unclear are the biological mechanisms that might be exacerbating tau deposition in female individuals.”

One factor appears to be the use of exogenous hormones, via HT, according to the authors. The Women’s Health Initiative found, however, that HT use—especially estrogen plus progestin—was associated with approximately a twofold higher incidence of probable dementia relative to placebo, especially if initiated proximate to menopause. Before those findings, the prevalence of HT use in postmenopausal female individuals was about 46% but dropped to 14.6% after publication.

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