Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood^1,2,3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology.

阿尔茨海默病是全世界痴呆症的主要原因，但其跨大脑区域病理进展的细胞途径仍然知之甚少^1,2,3 。在这里，我们报告了老年人大脑中六个不同大脑区域的单细胞转录组图谱，涵盖了来自 48 名患有和未患有阿尔茨海默病的个体的 283 个死后人类大脑样本的 130 万个细胞。我们鉴定了 76 种细胞类型，包括星形胶质细胞和兴奋性神经元的区域特异性亚型，以及丘脑特有且与典型抑制亚类不同的抑制性中间神经元群体。我们确定了阿尔茨海默病特定大脑区域中易受影响的兴奋性和抑制性神经元群体，并提供了 Reelin 信号通路参与调节这些神经元脆弱性的证据。我们开发了一种可扩展的方法来发现基因模块，我们用它来识别阿尔茨海默病中改变的细胞类型特异性和区域特异性模块，并注释与不同病理变量相关的转录组差异。我们确定了一个与阿尔茨海默病病理学认知弹性相关的星形胶质细胞程序，将星形胶质细胞中的胆碱代谢和多胺生物合成与晚年认知功能的保留联系起来。我们的研究共同开发了衰老人类大脑的区域图谱，并提供了关于细胞脆弱性、对阿尔茨海默病病理学的反应和恢复力的见解。