Potential role of TNFRSF12A in linking glioblastoma and alzheimer’s disease via shared tumour suppressor pathways

Abstract

Abstract Tumor suppressor genes (TSGs) are critical regulators of cellular homeostasis and are extensively studied in cancer biology. However, their roles in neurodegenerative diseases, particularly Alzheimer’s disease (AD), remain poorly understood. Recent evidence of an inverse association between cancer and AD suggests the existence of shared molecular mechanisms. We conducted an integrative analysis to identify TSGs with potential involvement in both AD and glioblastoma (GBM), using Mendelian randomization, transcriptomic profiling (bulk and single-cell RNA-seq), cell–cell communication inference, and in vitro validation. Among 1,217 TSGs screened, TNFRSF12A was consistently dysregulated in both GBM and AD datasets. Further analysis revealed its association with immune-related pathways and transcriptional programs relevant to both diseases. Knockdown of TNFRSF12A in glioma cells altered the expression of genes associated with amyloid precursor protein (APP) processing and Wnt signaling pathways. This study identifies TNFRSF12A as a cross-disease candidate gene in GBM and AD, based on transcriptomic convergence and partial functional validation. Our findings suggest that TSGs may contribute to shared molecular programs in neurodegeneration and cancer, and warrant further mechanistic investigation.