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

Abstract

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 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.

Figure 1.. Association of Age at Menopause With Neocortical β-Amyloid Positron Emission Tomography Signal to Predict Regional Tau Positron Emission Tomography Signal in Cognitively Unimpaired Female Individuals

A, Regions are derived from the Harvard-Oxford atlas on a Montreal Neurological Institute brain template. Brown indicates lateral occipital lobe; dark blue, amygdala; green, inferior temporal gyrus; light blue, entorhinal cortex; light green, temporal fusiform gyrus; red, superior parietal lobe; yellow, temporo-occipital lobe. B, Standard uptake volume ratio (SUVR) values by region are shown. Neocortical ¹¹C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) values to the right of the dashed line demonstrate when along the β-amyloid positron emission tomography spectrum age at menopause is associated with tau positron emission tomography P < .05. DVR values and equivalent Centiloid are reported. Age at menopause was specified as a continuous measure in the statistical models, with age bands specified above for visual purposes.

Figure 2.. Association of Timing of Hormone Therapy (HT) With Regional Tau Positron Emission Tomography Signal in Cognitively Unimpaired Females, Collapsed Across Neocortical β-Amyloid

HT 1 or more years before age at menopause is indicated in gray. HT (n = 27) within 5 years after age at menopause is indicated in blue (n = 52). Five or more years after age at menopause is indicated in orange (n = 10). SUVR indicates standard uptake volume ratio. ^aP = .01. ^bP = .001.