Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction

Aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is closely associated with neuronal death and cognitive decline in Alzheimer’s disease (AD). To define the signatures that distinguish between aggregation-prone and resistant cell states in AD, we developed a FACS-based method for the high-throughput isolation and transcriptome profiling of individual cells with cytoplasmic aggregates and profiled 63,110 somas from human AD brains. By comparing NFT-bearing and NFT-free somas within and across neuronal subtypes, we identified the cell-type-specific and shared states. NFT-bearing neurons shared a marked upregulation of genes associated with synaptic transmission, including a core set of 63 genes enriched for synaptic vesicle cycle and transsynaptic signaling, whereas glucose metabolism and oxidative phosphorylation changes were highly neuronal-subtype-specific. Apoptosis was modestly enriched in NFT-bearing neurons despite the strong link between tau and cell death. Our datasets provide a resource for investigating tau-mediated neurodegeneration and a platform for biomarker and drug target discovery.