Women show disproportionate burden of Alzheimer’s disease (AD) pathology and higher AD dementia prevalences compared to men, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunologic functioning, and neuroimmune processes are implicated in AD 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 modeling, 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%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 women. 57% (95%CI 22-100) of the effect of amyloid-β on tau was mediated through microglial activation in women, compared to 19% (95%CI 0-64) in men. 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 women, 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). In contrast, in men, 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 women. In contrast, in men, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for AD pathogenesis in women. Determining sex-specific vulnerabilities to AD development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

中文翻译：

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小胶质细胞激活对老年人阿尔茨海默病蛋白病的性别特异性影响

与男性相比，女性表现出不成比例的阿尔茨海默病 (AD) 病理学负担和更高的 AD 痴呆患病率，但驱动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 AD 发生有关。使用来自人脑组织的神经病理学指标，我们研究了小胶质细胞激活对淀粉样蛋白和 tau 之间关系的中介作用，以及它如何因性别而异。来自 Rush Memory and Aging Project 的 187 名死者（64% 为女性；89 名平均死亡年龄；62% 为非痴呆症）完成了神经病理学评估，并对脑组织进行了小胶质细胞激活、淀粉样蛋白-β 和 tau 的量化。通过免疫组织化学 (HLA-DP-DQ-DR) 和形态学分期（I、II 或 III 期）确定形态学激活的小胶质细胞的比例。淀粉样蛋白-β 和 tau 负荷通过免疫组织化学（分别为 M00872 或 AT8）进行量化。使用因果反事实建模，我们估计了小胶质细胞激活对整个样本中淀粉样蛋白-β 与 tau 关系的中介作用，并按性别分层（淀粉样蛋白-β → 小胶质细胞激活→ tau）。替代模型测试了小胶质细胞激活作为促发事件的作用（小胶质细胞激活→淀粉样蛋白-β→tau）。在整个样本中，小胶质细胞激活显着介导了 33% (95%CI 10-67) 的淀粉样蛋白-β 和 tau 之间的关系；分层分析表明，这种影响在女性中更强，并且仅在统计上显着。在女性中，57% (95%CI 22-100) 的淀粉样蛋白-β 对 tau 蛋白的作用是通过小胶质细胞激活介导的，而在男性中这一比例为 19% (95%CI 0-64)。区域分析表明，中介效应是由更大的皮层与皮层下小胶质细胞激活驱动的。关系独立于脑血管疾病指数。替代模型表明，在女性中，小胶质细胞激活是淀粉样蛋白-β 与 tau 关系之前的显着暴露（中介效应：50%，95%CI 23-90），并且与 tau 负荷直接相关（小胶质细胞直接效应：50%， 95%CI 10-77)。相反，在男性中，只有小胶质细胞激活对 tau 的直接影响达到显着性 (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双向双向关系，这显着解释了女性的 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 之间的直接独立（非中介）关系。小胶质细胞激活可能对女性 AD 发病机制异常重要。确定 AD 发展的性别特异性脆弱性既可以为基础病理生理学提供信息，也可以为这种异质性疾病提供精确的健康方法。