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- W4210366345 abstract "Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, despite recent single-cell transcriptomic analyses of human AD brain tissue, it remains unclear which neuronal subtypes are most vulnerable to degeneration. Here we applied cell-type proportion estimation methods to multiple RNA sequencing (RNAseq) datasets derived from human postmortem brain to identify the neuronal subtypes most strongly associated with AD.Postmortem bulk-brain RNAseq data collected from three AD studies were analyzed (n=953), comprising six datasets of different neocortical regions. Relative cell type proportions were estimated for each brain sample using the markerGeneProfile package and marker genes for specific neuronal subtypes derived from ultra-high depth single-nucleus RNAseq (Hodge et al., 2019). Linear models were used to test associations of cell-type proportion estimations (CTPs) with AD diagnosis in each dataset separately, followed by random-effects meta-analysis. Pseudo-bulk investigation of the Mathys et al. (2019) single-nucleus RNAseq dataset was used to further validate findings. Follow-up in the Religious Orders Study and Memory and Aging Project (ROS/MAP) cohorts (n=593) permitted the identification of specific neuropathologies associated with each neuronal subtype.Meta-analysis revealed several neuronal subtypes significantly associated with AD, with the strongest signals from intra-telencephalic (IT) excitatory neurons (meta p=4.82x10-13 ) and somatostatin (SST) inhibitory neurons (meta p= 1.55x10-10 ). Pseudo-bulk single-nucleus analysis suggested that these signals are most likely due to differences in cell proportions rather than differences in expression of any predominant marker gene for each class. In-depth analysis of CTPs in ROS/MAP consistently implicated a decrease in IT and SST CTPs with increasing amyloid and tau neuropathology, as well as more severe cognitive decline prior to death.Decreases in SST and IT neuron subtypes, estimated from bulk RNAseq data, were significantly associated with AD diagnosis across multiple cortical regions. The SST signal in particular is robust to the exclusion of the SST mRNA from CTP calculations, suggesting the pathological relevance of a loss of SST-expressing neurons rather than a downregulation of the SST gene specifically. These findings support seminal work implicating somatostatin in the pathogenesis of AD and helps to re-focus our current understanding of neuronal vulnerability in AD." @default.
- W4210366345 created "2022-02-08" @default.
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- W4210366345 date "2021-12-01" @default.
- W4210366345 modified "2023-09-27" @default.
- W4210366345 title "Robust cell-type-specific associations with Alzheimer's disease within excitatory and inhibitory neuronal subclasses." @default.
- W4210366345 doi "https://doi.org/10.1002/alz.052252" @default.
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- W4210366345 hasPublicationYear "2021" @default.
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