A single-cell transcriptomic atlas of six brain regions in the aged human brain has been developed to understand the cellular mechanisms underlying Alzheimer's disease (AD). The study analyzed 1.3 million cells from 283 post-mortem brain samples across 48 individuals, both with and without AD, identifying 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons, and a unique inhibitory interneuron population in the thalamus. The study found vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in AD, and provided evidence that the Reelin signaling pathway is involved in modulating the vulnerability of these neurons. A scalable method for discovering gene modules was developed, which was used to identify cell-type-specific and region-specific modules altered in AD and to annotate transcriptomic differences associated with diverse pathological variables. An astrocyte program associated with cognitive resilience to AD pathology was identified, linking choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. The study also identified regional differences in neuronal and glial subtype alterations in AD and in cognitive resilience to AD pathology. The study developed a multiregion atlas of AD, providing insights into cellular vulnerability, response, and resilience to AD pathology. The study identified 32 astrocyte modules, including an astrocyte-wide program marked by GPM6A and GPC5 and subtype- and region-specific identity programs. The study also identified genes associated with neuronal vulnerability in AD, including Reelin signaling pathway genes, and found that vulnerable subtypes share marker genes that might mediate their vulnerability. The study identified regional differences in gene expression and function specific to individuals with pathologic AD, and found that astrocytes and inhibitory and excitatory neurons showed the highest number of differentially expressed genes (DEGs) across all regions. The study also identified genes associated with AD pathology burden in the PFC across 427 individuals, and found that a significant component of the glial AD response is consistent across regions. The study identified genes associated with different pathologies, including NFTs and neuritic amyloid-β plaque burden, and found that these pathologies induce distinct transcriptional responses. The study identified genes associated with cognitive resilience (CR) in AD, and found that astrocytes were the only cell type with a consistently high number of genes associated with CR across all measures tested. The study identified CR-associated genes, including GPX3, HMGN2, NQO1, and ODC1, which possess or promote antioxidant activities and were positively associated with cognitive function. The study also identified genes involved in choline metabolism and polyamine biosynthesis that were associated with CR in astrocytes. The study validated the choline pathway genes PNPLA6, GPCPD1, and CHDH using in situ hybridization. The study provided insights into the molecular mechanisms underlyingA single-cell transcriptomic atlas of six brain regions in the aged human brain has been developed to understand the cellular mechanisms underlying Alzheimer's disease (AD). The study analyzed 1.3 million cells from 283 post-mortem brain samples across 48 individuals, both with and without AD, identifying 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons, and a unique inhibitory interneuron population in the thalamus. The study found vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in AD, and provided evidence that the Reelin signaling pathway is involved in modulating the vulnerability of these neurons. A scalable method for discovering gene modules was developed, which was used to identify cell-type-specific and region-specific modules altered in AD and to annotate transcriptomic differences associated with diverse pathological variables. An astrocyte program associated with cognitive resilience to AD pathology was identified, linking choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. The study also identified regional differences in neuronal and glial subtype alterations in AD and in cognitive resilience to AD pathology. The study developed a multiregion atlas of AD, providing insights into cellular vulnerability, response, and resilience to AD pathology. The study identified 32 astrocyte modules, including an astrocyte-wide program marked by GPM6A and GPC5 and subtype- and region-specific identity programs. The study also identified genes associated with neuronal vulnerability in AD, including Reelin signaling pathway genes, and found that vulnerable subtypes share marker genes that might mediate their vulnerability. The study identified regional differences in gene expression and function specific to individuals with pathologic AD, and found that astrocytes and inhibitory and excitatory neurons showed the highest number of differentially expressed genes (DEGs) across all regions. The study also identified genes associated with AD pathology burden in the PFC across 427 individuals, and found that a significant component of the glial AD response is consistent across regions. The study identified genes associated with different pathologies, including NFTs and neuritic amyloid-β plaque burden, and found that these pathologies induce distinct transcriptional responses. The study identified genes associated with cognitive resilience (CR) in AD, and found that astrocytes were the only cell type with a consistently high number of genes associated with CR across all measures tested. The study identified CR-associated genes, including GPX3, HMGN2, NQO1, and ODC1, which possess or promote antioxidant activities and were positively associated with cognitive function. The study also identified genes involved in choline metabolism and polyamine biosynthesis that were associated with CR in astrocytes. The study validated the choline pathway genes PNPLA6, GPCPD1, and CHDH using in situ hybridization. The study provided insights into the molecular mechanisms underlying