Cell type transcriptomic modules reveal shared molecular mechanisms in Alzheimer's and Parkinson's disease

Historically, Alzheimer's disease (AD) and Parkinson's disease (PD) have been investigated as 2 distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single-gene centric studies, such as differential gene expression analyses, have struggled to unravel the molecular basis for the observed pathological links between AD and PD.

We tailor a latent factor framework to analyze synchronous gene co-expression changes in AD or PD at sub-cell-type resolution. Utilizing large, single-nucleus transcriptomics datasets in AD (70,634 nuclei) and PD (340,902 nuclei) from postmortem human brains, we systematically extract and juxtapose disease-critical molecular signatures in the brain. Our transcriptomic analysis reveals shared molecular programs between AD and PD that localize to specific glial and neuronal cell types. In neurons, convergent gene groups in AD and PD relate to cytoskeletal dynamics and mitochondrial stress mechanisms. In microglia, overlapping gene modules implicate T cell activation mechanisms and synapse pruning pathways. In parallel, AD- and PD-associated gene groups in astrocytes are involved in heavy metal processing; oligodendrocytes highlight convergent dysregulation in myelin synthesis. Additionally, our analysis reveals apolipoprotein E gene (an AD risk gene), and the synuclein alpha gene (a PD risk gene) to have disease predictive roles in both AD- and PD-associated gene modules.

Our multi-module sub-cell-type approach offers novel insights into the molecular basis of shared neuropathology in AD and PD.