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Premature Menopause & HRT, Alzheimers - Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography
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new study may have uncovered a piece or two of the puzzle. Women who underwent early (age 40 to 45) or premature (before age 40) menopause or women who began hormone replacement therapy more than five years after menopause had higher levels of tau in their brains, according to the study published Monday in the journal JAMA Neurology.
Tau tangles, along with plaques made up of beta-amyloid proteins, are hallmark signs of Alzheimer's disease.
"This is the first study showing a delayed use of hormone therapy seems to be associated with increased levels of Alzheimer's disease markers in the brain," said lead author Gillian Coughlan, a research fellow in neurology at Massachusetts General Hospital in Boston.
Female individuals exhibited higher cortical tau than age-matched males, which was exacerbated in the setting of high neocortical Aβ. In the setting of high neocortical Aβ (approximately ≥20 Centiloids), levels of tau were associated with a self-report younger age at menopause and a history of menopausal HT. Female individuals with late initiation of menopausal HT, more than 5 years after age at menopause, showed higher levels of tau, relative to those who initiated near their age at menopause. Cognitive performance at the tau scan was slightly lower in those with younger age at menopause and late HT use, compared with older age at menopause and early HT use.
JAMA Neurol.
Key Points
Are female sex, earlier age at menopause, and hormone therapy (HT) use associated with the deposition of tau pathology?
Findings In this cross-sectional study, female sex, earlier age at menopause, and HT use were significantly associated with higher regional tau in the context of high β-amyloid, as measured on the positron emission tomography signal. Late initiation of HT following menopause onset may underpin the association between HT use and the elevated tau positron emission tomography signal.
Meaning Earlier age at menopause and the late initiation of HT following menopause onset may be important sex-specific risk factors that underlie sex differences in tau deposition.
Postmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high β-amyloid (Aβ). The biological mechanisms associated with higher tau deposition in female individuals remain elusive.
Objective To examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aβ, both measured with positron emission tomography (PET).
Design, Setting, and Participants This cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021.
Exposures Premature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported.
Main Outcomes and Measures Seven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aβ PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET.
Results Of 292 cognitively unimpaired individuals, there were 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 Aβ, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized β = -0.41; 95% CI, -0.97 to -0.32; P < .001), earlier age at menopause (standardized β = -0.38; 95% CI, -0.14 to -0.09; P < .001), and HT use (standardized β = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aβ compared with male sex, later age at menopause, and HT nonuse. Affected regions included medial and lateral regions of the temporal and occipital lobes. Late initiation of HT (>5 years following age at menopause) was associated with higher tau PET compared with early initiation (β = 0.49; 95% CI, 0.27-0.43; P = .001).
Conclusions and Relevance In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aβ. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aβ elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.

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