Cell-death pathways and tau-associated neuronal vulnerability in Alzheimer's disease.

Neuronal loss is the ultimate driver of neural system dysfunction in Alzheimer's disease (AD). We used single-nucleus RNA sequencing and neuropathological phenotyping to elucidate mechanisms of neurodegeneration in AD by identifying vulnerable neuronal populations and probing for their differentially expressed genes. Evidenced by transcriptomic analyses and quantitative tau immunoassays of human AD and non-AD brain tissue, we identified a neuronal population especially vulnerable to tau pathology. Multiplexed immunohistochemistry and in situ hybridization (CBLN2 and LINC00507) validated the presence of the tau-vulnerable neuronal population and revealed a propensity of this population to bear tau pathology. Differentially expressed genes associated with phospho-tau pathology in these neurons revealed genes involved in apoptosis, cell-component dissociation (e.g., autophagosome maturation and actin filament depolymerization), and regulation of vesicle-mediated transport.