Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals key associations with AD pathology.

Alzheimer's disease, the leading cause of dementia in the elderly, is a neurodegenerative disorder that has been studied to uncover therapeutic pathways through its molecular and cellular hallmarks. Here, we present a comprehensive investigation of cellular heterogeneity from the temporal cortex region of 40 individuals, comprising healthy donors and individuals with differing AD pathology. Using single-nucleus transcriptomic analysis of 430,271 nuclei from both gray and white matter of these individuals, we identified cell type-specific subclusters in both neuronal and glial cell types with varying degrees of association with AD pathology. We extended this analysis by performing multiplexed in situ hybridization using the CARTANA platform, capturing 155 genes in 13 individuals with differing tau pathology. We not only replicated snRNA data key findings from our spatial data analysis but also identified a set of cell type-specific genes that show selective enrichment or depletion near pathological inclusions.