Canonical Pathways Rewiring in Alzheimer’s Disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by the simultaneous disruption of interconnected molecular pathways, yet the structural mechanisms underlying this transcriptional disintegration remain poorly characterized. To address this, we constructed condition-specific gene co-expression networks from DLPFC bulk RNA-seq data, using a mutual-information (MI) framework with infomap community partitioning. Functional enrichment of network communities via Ingenuity Pathway Analysis (IPA) identified GABAergic signaling, SNARE complex assembly, Synaptogenesis, and neurexin and neuroligin interactions as significantly overrepresented pathways. Integration of node degree with condition-specific average expression revealed coordinated topological centralization of key synaptic genes—including NRXN2, LRRTM1, DLGAP3, and SHANK1—alongside a widespread transcriptional downregulation in GABAergic and Synaptogenesis modules. A shortest-path analysis revealed a consistent expansion of intra-pathway distances across all evaluated canonical pathways in AD, a pattern statistically consistent with reduced local co-expression cohesion. These findings reframe Late-Onset Alzheimer’s Disease (LOAD) as an active structural-rewiring process, in which the observed topological centralization pattern seems to be consistent with a consolidation of co-expression around synaptic components, though we cannot exclude that shifts in cellular composition contribute to this signal in bulk RNA-seq data.