Neuroimmune Transcriptomic Convergence Identifies Druggable Immune Hubs Linking Alzheimer’s Disease and Sjögren’s Syndrome

Background Alzheimer's disease (AD) and primary Sjögren's syndrome (pSS) share epidemiological links and neuroimmune features, yet their common molecular signatures remain undefined. We performed an integrative transcriptomic analysis to identify shared differentially expressed genes (DEGs), pathways, regulatory networks, and druggable targets linking systemic autoimmunity to neurodegeneration.​ Methods Using GEO datasets GSE97760 (AD whole blood, n = 19) and GSE40611 (pSS salivary gland, n = 35), we identified DEGs (adj. p < 0.05, |log2FC|>1) via limma/GEO2R and common DEGs (n = 7) via Venn analysis. Functional enrichment employed Metascape (GO/KEGG/Reactome); PPI networks used STRING/NetworkAnalyst (hub genes: degree > 15). Regulatory networks integrated miRTarBase (miRNA-hub), JASPAR (TF-hub), and DGIdb (drug-hub) interactions.​ Results Seven shared DEGs (PTPRC, SH2D1A, GVINP1, FCRL5, MIAT, MIER3, KBTBD8) enriched in immune response (GO:0002376), complement activation, interferon/cytokine signaling, antigen presentation, and B/T-cell activation (FDR < 0.05). PPI analysis confirmed PTPRC (CD45) and SH2D1A (SAP) as hubs in lymphocyte/microglial modules. miRNA networks highlighted hsa-miR-144/548a-3p/590-3p targeting multiple hubs; TFs (STAT1/3, NFKB1, RELA, IRF2) regulated > 3 hubs. DGIdb revealed PTPRC interactions with corticosteroids (prednisone) and SH2D1A with emapalumab (IFNγ blocker), nominating immune-modulatory repurposing candidates.​ Conclusions This study uncovers an immune-centric regulatory architecture—anchored by PTPRC/SH2D1A hubs—converging AD and pSS via shared neuroinflammatory pathways. These findings illuminate neuroimmune crosstalk in comorbidity and propose cross-disease therapeutics, warranting validation in larger cohorts.​