Association of Age at Menopause and Hormone Therapy Use With Tau and -Amyloid Positron Emission Tomography

IMPORTANCE 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 beta-amyloid (A beta). 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 A beta, 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 showsex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and A beta 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 A beta, and 106 (36.3%) were APOEe4 carriers. There were 98 female HT users (52.2%) (past/current). 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 associated with higher regional tau PET in individuals with elevated A beta 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 (beta = 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 A beta. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical A beta elevated. These observational findings suggest