Network-based analysis on genetic variants reveals the immunological mechanism underlying Alzheimer's disease

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the impairment of cognitive function and loss of memory. Previous studies indicate an essential role of immune response in AD, but the detailed mechanisms remain unclear. In this study, we obtained 1664 credible risk variants (CRVs) based on the most significant SNP detected by International Genomics of Alzheimer's Project, from which 99 genes (CRVs-related genes) were identified. Function analysis revealed that these genes were mainly involved in immune response and amyloid-β and its precursor metabolisms, indicating a potential role of immune response in regulating neurobiological processes in the etiology of neurodegenerative disease. Pathway crosstalk analysis revealed the complicated connections between immune-related pathways. Further, we found that the CRVs-related genes showed temporal-specific expression in the thalamus in adolescence developmental period. Cell type-specific expression analysis found that CRVs-related genes might be specifically expressed in brain cells such as astrocytes and oligodendrocytes. Protein-protein interaction network analysis identified the highly interconnected 'hub' genes, all of which were susceptible loci of AD. These results indicated that the CRVs may exert a potential influence in AD by regulating immune response, thalamus development, astrocytes activities, and amyloid-β binding. Our results provided hints for further experimental verification of AD pathophysiology.