Abstract
Abstract Background Alzheimer’s disease (AD) and Parkinson’s disease (PD) have overlapping characteristics in terms of symptoms and brain pathology. Understanding the similarities in these diseases could lead to more effective treatments. While there is only limited evidence for genetic overlap between the two, enrichment of heritability in genetic regions that are related to microglia has been found in both diseases. However, most of the transcriptomics studies published on AD and PD employed postmortem brains, which obscures the identification of alteration of gene expression within individual cell types. Method Here we used single‐nucleus transcriptomics to examine over eight million nuclei generated from prefrontal cortex samples of over a thousand postmortem donors with AD, PD, both diseases and controls. Then, we built gene regulatory networks (GRNs) to detect the shared gene expression alterations in all major cell types and detected key drivers within each module. Result Examining multiple levels of transcriptomic organization, such as gene expression and GRNs for both protein‐coding and noncoding genes, provided a comprehensive understanding of the molecular pathology of AD and PD. Our analysis revealed cell‐specific modules linked to shared and distinct mechanisms of both diseases. Network‐derived signatures showed cell‐type specificity, implicating regulatory regions within AD and PD genetic risk loci that participate in a variety of biological pathways as well as changes in TF regulation. Conclusion The integration of transcriptomic and genetic data from AD and PD provides a quantitative, genome‐wide resource for mechanistic insight and potential therapeutic development. Funding : U01NS125580, R01AG067025, AARF‐21‐722200