Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.

星形胶质细胞对大脑稳态至关重要，但它们沿阿尔茨海默病 （AD） 神经病理学时空进展的变化仍未得到探索。在这里，我们对来自 5 个大脑区域的 628,943 个星形胶质细胞进行了单核 RNA 测序，这些星形胶质细胞代表了 32 名供体的 AD 病理学的刻板印象进展，跨越了整个正常衰老到严重 AD 连续体。我们绘制了几个独特的星形胶质细胞亚簇，它们在 AD 脆弱的神经网络（空间轴）或 AD 病理阶段（时间轴）上表现出对神经病理学的不同反应。稳态、中间和反应性星形胶质细胞的比例仅沿空间轴变化，而其他两个亚簇沿时间轴变化。其中一个是富含营养因子的子集群，沿病理阶段下降，而另一个在晚期增加，但在末期恢复到基线水平，表明对长期暴露于神经病理学的反应耗尽。我们的研究强调了 AD 中星形胶质细胞反应的复杂动力学。