This study presents a comprehensive single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem samples across 48 individuals, including those with and without Alzheimer's disease (AD). The atlas identifies 76 cell types, including region-specific subtypes of astrocytes, excitatory neurons, and inhibitory interneurons. Key findings include the identification of vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in AD, and the involvement of the Reelin signaling pathway in modulating their vulnerability. The study also develops a scalable method for discovering gene modules and identifies cell-type-specific and region-specific modules altered in AD. Additionally, it identifies an astrocyte program associated with cognitive resilience to AD pathology, linking choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. The atlas provides insights into cellular vulnerability, response, and resilience to AD pathology across different brain regions.This study presents a comprehensive single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem samples across 48 individuals, including those with and without Alzheimer's disease (AD). The atlas identifies 76 cell types, including region-specific subtypes of astrocytes, excitatory neurons, and inhibitory interneurons. Key findings include the identification of vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in AD, and the involvement of the Reelin signaling pathway in modulating their vulnerability. The study also develops a scalable method for discovering gene modules and identifies cell-type-specific and region-specific modules altered in AD. Additionally, it identifies an astrocyte program associated with cognitive resilience to AD pathology, linking choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. The atlas provides insights into cellular vulnerability, response, and resilience to AD pathology across different brain regions.