Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston.
Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, School of Medicine and Public Health, Madison.
JAMA Neurol. 2023 May 1;80(5):462-473. doi: 10.1001/jamaneurol.2023.0455.
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.
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.
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.
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.
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).
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.
绝经后女性约占所有阿尔茨海默病患者的 70%。先前的文献表明，与年龄匹配的男性相比，认知正常的绝经后女性的 tau 水平升高，尤其是在高β-淀粉样蛋白（Aβ）的情况下。与女性个体中 tau 沉积增加相关的生物学机制仍不清楚。
检查性别、绝经年龄和激素治疗（HT）使用与特定 Aβ 水平下的区域 tau 的相关性，两者均通过正电子发射断层扫描（PET）进行测量。
设计、地点和参与者：这项横断面研究包括参加威斯康星州阿尔茨海默病预防注册处的参与者。分析了至少有 1 个 18F-MK-6240 和 11C-Pittsburgh 复合 B PET 扫描的认知正常的男性和女性参与者。数据收集于 2006 年 11 月至 2021 年 5 月之间。
早绝经（绝经年龄小于 40 岁）、中绝经（绝经年龄 40-45 岁）和晚绝经（绝经年龄大于 45 岁）和 HT 用户（当前/过去使用）和 HT 非用户（当前/过去未使用）。暴露情况是自我报告的。
7 个 tau PET 区域，这些区域在颞叶、顶叶和枕叶之间表现出性别差异。主要分析通过一系列线性回归检查了性别、绝经年龄或 HT 与 Aβ PET 对区域 tau PET 的相互作用。次要分析研究了 HT 时间与绝经年龄对区域 tau PET 的影响。
在 292 名认知正常的个体中，有 193 名女性（66.1%）和 99 名男性（33.9%）。tau 扫描的平均（范围）年龄为 67（49-80）岁，52 人（19%）有异常的 Aβ，106 人（36.3%）是 APOEε4 携带者。有 98 名女性 HT 用户（52.2%）（过去/现在）。女性性别（标准化β=−0.41；95%置信区间，−0.97 至−0.32；P<0.001）、更早的绝经年龄（标准化β=−0.38；95%置信区间，−0.14 至−0.09；P<0.001）和 HT 使用（标准化β=0.31；95%置信区间，0.40-1.20；P=0.008）与 Aβ 升高的个体中较高的区域 tau PET 相关，而男性性别、较晚的绝经年龄和 HT 不使用相关。受影响的区域包括颞叶和枕叶的内侧和外侧区域。与早期开始 HT（绝经后>5 年）相比，晚期开始 HT 与较高的 tau PET 相关（β=0.49；95%置信区间，0.27-0.43；P=0.001）。
在这项研究中，女性与年龄匹配的男性相比，tau 水平更高，尤其是在 Aβ 升高的情况下。在女性中，更早的绝经年龄和晚期开始 HT 与 tau 易感性增加有关，尤其是当皮质 Aβ 升高时。这些观察性发现表明，女性个体的某些亚组可能面临更高的病理负担风险。
