Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer’s disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([¹¹C]PBR28), amyloid-β (Aβ) ([¹⁸F]AZD4694) and tau ([¹⁸F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [¹¹C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages.

令人信服的实验证据表明，小胶质细胞的激活与阿尔茨海默病 (AD) 中 tau 缠结在新皮质上的扩散有关。我们测试了小胶质细胞激活的空间传播和 tau 积累在活的人脑中以 Braak 样模式共定位的假设。我们通过正电子发射断层扫描脑成像研究了 130 名跨越衰老和 AD 临床谱的个体，用于小胶质细胞激活 ([ ¹¹ C]PBR28)、淀粉样蛋白-β (Aβ) ([ ¹⁸ F]AZD4694) 和 tau ([ ¹⁸ F]MK- 6240) 病理。我们进一步评估了骨髓细胞 2 ( TREM2 ) 脑脊液 (CSF) 浓度和脑基因表达模式上表达的小胶质细胞触发受体。我们发现 [ ¹¹C]PBR28 与 CSF 可溶性 TREM2 相关，并显示出类似于TREM2基因表达的区域分布。网络分析显示，在 Braak 样阶段之后，小胶质细胞激活和 tau 相互分层相关。回归分析表明，纵向 tau 传播途径取决于基线小胶质细胞网络，而不是 tau 网络电路。Aβ、tau 和小胶质细胞异常的共同发生是我们研究人群中认知障碍的最强预测因子。我们的研究结果支持一个模型，其中 Aβ 和活化的小胶质细胞之间的相互作用决定了 tau 在 Braak 阶段的传播速度。