Integrating Gene and Protein Expression Reveals Perturbed Functional Networks in Alzheimer’s Disease

Asymptomatic and symptomatic Alzheimer’s disease (AD) subjects may present with equivalent neuropathological burdens but have significantly different antemortem cognitive decline rates. Using the transcriptome as a proxy for functional state, we selected 414 expression profiles of symptomatic AD subjects and age-matched non-demented controls from a community-based neuropathological study. By combining brain tissue-specific protein interactomes with gene networks, we identified functionally distinct composite clusters of genes that reveal extensive changes in expression levels in AD. Global expression for clusters broadly corresponding to synaptic transmission, metabolism, cell cycle, survival, and immune response were downregulated, while the upregulated cluster included largely uncharacterized processes. We propose that loss of EGR3 regulation mediates synaptic deficits by targeting the synaptic vesicle cycle. Our results highlight the utility of integrating protein interactions with gene perturbations to generate a comprehensive framework for characterizing alterations in the molecular network as applied to AD. [Display omitted] •RNA expression profiling of 414 Alzheimer’s disease and non-demented controls•Integration of transcriptomic profiles with brain tissue-specific protein interactome•Revealed biologically distinct clusters by Louvain algorithm for community detection•Characterized transcriptional regulators across all clusters Canchi et al. reveal the transcriptomic dynamics of clinically and neuropathologically confirmed Alzheimer’s disease subjects by integrating brain tissue-specific proteome data with gene network analysis. They identify perturbed biological processes and provide insights into the interactions between molecular mechanisms in symptomatic Alzheimer’s disease.