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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 NFTbearing 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 taumediated neurodegeneration and a platform for biomarker and drug target discovery.

Alzheimer’s disease (ad) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology meta-analytical approach across three human ad cohorts, encompassing six cortical brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies, and quantitative trait loci to further characterize the genetic architecture of ad. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust ad-associated dysregulation of the transcriptome, unaltered in normal human aging. We assess the cell-type specificity of ad gene co-expression changes and estimate cell-type proportion changes in human ad by integrating co-expression modules with single-cell transcriptome data generated from 27 321 nuclei from human postmortem prefrontal cortical tissue. We also show that genetic variants of ad are enriched in a microglial ad-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human ad gene expression datasets, which can be easily accessed using our online resource (https://swaruplab.bio.uci.edu/consensusAD).