Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition. METHODS: We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French). RESULTS: We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (ß = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; ß = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; ß = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; ß = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (ß = -0.005, 95% CI -0.032 to 0.021, p = 0.69). DISCUSSION: Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.

Association of Age at Menopause and Hormone Therapy Use With Tau and ß-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 ß-amyloid (Aß). 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 Aß, 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 Aß 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 Aß, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized ß = -0.41; 95% CI, -0.97 to -0.32; P < .001), earlier age at menopause (standardized ß = -0.38; 95% CI, -0.14 to -0.09; P < .001), and HT use (standardized ß = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aß 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 (ß = 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 Aß. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aß elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.