Single-Cell Cortical Transcriptomics Reveals Common and Distinct Pathway Activity Signatures in Alzheimer’s and Parkinson’s Disease#

Authors#

Sophie Le Bars, Enrico Glaab

Abstract#

Neurodegenerative disorders, including the two most prevalent, Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by pronounced neuronal loss and significant deterioration in quality of life. While AD and PD exhibit many distinct neuropathological symptoms and clinical manifestations, they also share common molecular features and comorbidities, such as mitochon- drial dysfunction and progressive cognitive decline. To uncover conserved and unique disease pathways, we performed a comparative single-cell transcriptomic analysis of post-mortem cortical tissue from AD, PD and matched healthy con- trols. We characterized shared and distinct cell-type-specific features at the level of individual genes, pathways, and cellular sub-networks, identifying common coordinated changes that may reflect shared susceptibility mechanisms and sig- natures of discriminative molecular markers. The results confirm the presence of disease-specific, shared, and oppositely-regulated differentially expressed genes across multiple cell types, including unique cell-type-specific disease marker genes. Shared significant genes were over-represented in processes associated with the regulation of nervous system development, axon growth, and the Wnt signal- ing pathway. Cell-type specific gene regulatory network analyses also highlighted putative target genes regulating shared disease pathways, such as TCF7L2 as a modulator of Wnt signaling in astrocytes. Overall, our study reveals conserved and unique gene signatures, pathways, and regulatory sub-networks in AD and PD. The findings offer insights into molecular commonalities and differences in these diseases and the regulation of coordinated pathway activity alterations, guiding future diagnostic and therapeutic strategies. Keywords: Single-Cell Cortical Transcriptomics Reveals Common and Distinct Pathway Activity Signatures in Alzheimer’s and Parkinson’s Disease