Network-based analysis of Alzheimer’s Disease genes using multi-omics network integration with graph diffusion

Alzheimer's Disease (AD) is a complex neurodegenerative disorder affecting millions worldwide. Despite extensive research, the mechanisms behind AD remain elusive. Many studies suggest that disease-responsible genes often act as hub genes in biological networks. However, this assumption requires further investigation in the context of AD. To examine the network characteristics of known AD genes, it is crucial to construct a highly confident network, which is challenging to achieve using a single data source. This work integrates multi-omics networks inferred from microarray, single-cell RNA sequencing, and single-nuclei RNA sequencing expression data, weighted with protein interaction and gene ontology information. We generate a high-quality integrated network by utilizing various inference methods and combining them through a graph diffusion-based integration approach. This network is then analyzed to investigate the properties of known AD-specific genes. Our findings reveal that AD genes are not always high-degree or central hub nodes in the network. Instead, these genes are distributed across different quartiles of degree centrality while maintaining significant interconnections for effective regulation. Furthermore, our study highlights that peripheral genes, often overlooked, also play crucial roles by connecting to relevant disease nodes and hub genes. These findings challenge the conventional understanding that AD-responsible genes are primarily the hub genes in the network, offering new insights into the complex regulatory mechanisms of AD and suggesting novel directions for future research.