TWAS-Derived Integrative Network Analysis Implicates RPS3–NFKBIA Regulatory Link in Japanese Alzheimer's Disease

Late-onset Alzheimer's disease (LOAD) has high heritability (60–80%), yet most genetic factors remain unexplained. Here, TWAS was performed using the largest Japanese LOAD cohort to date (8,036 samples), integrating GWAS with blood-based eQTL. Candidate genes were validated using independent RNA-seq data (n=692). PPI and GRN analyses identified 132 hub genes in both networks. The top 10 hub genes showed significant interconnectivity (PPI enrichment P = 4.19e−05), suggesting coordinated dysregulation of ribosomal and immune pathways in LOAD. These findings suggest a regulatory crosstalk between ribosomal and NF-κB pathway dysregulation and identify candidate genes for blood-based LOAD biomarkers.