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Abstract:
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Alzheimer’s disease with psychosis (AD+P) is associated with a much more rapid deterioration compared to those without psychosis. In this study, we used mass spectrometry to quantify hundreds of synaptic proteins from the dorsolateral prefrontal cortex (DLPFC) of 56 post-mortem AD samples. We performed differential expression analysis between AD+P and AD-P, in the presence of neuropathology variables, to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms. Moreover, we performed RNA-sequencing in an expanded cohort of 80 AD cases, to identify transcriptomic signatures that are associated with risk of psychosis in AD. Cell-type proportions were estimated using the non-negative least squares deconvolution approach (MIND). We also conducted gene-network analyses to identify mRNA modules that were differentially expressed between AD+P and AD-P. We built up connections between the proteomics data and the transcriptomic data. Finally, we constructed psychosis prediction model together with neuropathology burden, cell type proportions and the gene expression modules.
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