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 framework with Infomap community partitioning. Functional enrichment of network communities via Ingenuity Pathway Analysis (IPA) identified GABAergic signaling, SNARE complex assembly, Synaptogenesis, and Neurexins and Neuroligins 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. Shortest path analysis further demonstrated a consistent expansion of intra-pathway distances across all evaluated canonical pathways in AD, quantifying a progressive loss of local communication efficiency. These findings reframe LOAD as an active structural rewiring process, in which the transcriptional network consolidates remaining resources around essential synaptic components as a molecular signature of the pathological state.