Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Brain. 2022 Oct 21;145(10):3536-3545. doi: 10.1093/brain/awac257.
Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-β and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-β and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-β to tau relationship in the whole sample and stratified by sex (amyloid-β → microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-β → tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10-67] of the relationship between amyloid-β and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-β on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-β to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-β and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.
女性在阿尔茨海默病病理和更高的阿尔茨海默病痴呆患病率方面的负担不成比例，而导致这些脆弱性的机制尚不清楚。免疫功能存在性别二态性，神经免疫过程与阿尔茨海默病的发生有关。我们使用来自人类脑组织的神经病理学指标，研究了小胶质细胞激活在淀粉样蛋白和 tau 之间关系中的中介作用，以及它如何因性别而异。来自拉什记忆与衰老项目的 187 名死者（64%为女性；死亡时的平均年龄为 89 岁；62%无痴呆）完成了神经病理学评估，并对小胶质细胞激活、淀粉样蛋白-β 和 tau 进行了脑组织定量。通过免疫组织化学（HLA-DP-DQ-DR）和形态学分期（I 期、II 期或 III 期）确定形态激活的小胶质细胞的比例。通过免疫组织化学（分别为 M00872 或 AT8）定量淀粉样蛋白-β 和 tau 负担。使用因果反事实建模，我们估计了小胶质细胞激活在整个样本和按性别分层（淀粉样蛋白-β→小胶质细胞激活→tau）的情况下对淀粉样蛋白-β 与 tau 关系的中介效应。替代模型测试了小胶质细胞激活作为先发事件的作用（小胶质细胞激活→淀粉样蛋白-β→tau）。小胶质细胞激活在整个样本中显著介导了 33%[95%置信区间（CI）10-67]的淀粉样蛋白-β 与 tau 之间的关系；分层分析表明，这种影响在女性中更强，且仅具有统计学意义。与男性相比，女性中淀粉样蛋白-β 对 tau 的 57%（95%CI 22-100）的影响是通过小胶质细胞激活介导的，而男性中仅为 19%（95%CI 0-64）。区域分析表明，中介效应是由皮质与皮质下小胶质细胞激活的差异驱动的。这些关系独立于脑血管疾病指标。替代模型表明，在女性中，小胶质细胞激活既是淀粉样蛋白-β 与 tau 关系的重要暴露因素（中介效应：50%，95%CI 23-90），又是 tau 负担的直接相关因素（小胶质细胞直接效应：50%，95%CI 10-77）。相比之下，在男性中，只有小胶质细胞激活对 tau 的直接效应达到显著水平（74%，95%CI 32-100）（中介效应：26%，95%CI 0-68）。我们的模型表明，淀粉样蛋白-β 和小胶质细胞激活之间存在一种互惠的、双向关系，这在女性中显著解释了 tau 负担。相比之下，在男性中，观察到小胶质细胞激活或淀粉样蛋白-β 与 tau 之间直接独立（非中介）的关系。小胶质细胞激活可能在女性阿尔茨海默病发病机制中具有不成比例的重要性。确定女性对阿尔茨海默病发展的性别特异性脆弱性，不仅可以阐明其基本病理生理学机制，还可以支持针对这种异质性疾病的精准健康方法。
