Exploring the role of RALYL in Alzheimer’s disease reserve by network-based approaches

BACKGROUND: Alzheimer’s disease (AD) reserve theory is based on specific individual characteristics that are associated with a higher resilience against neurodegeneration and its symptoms. A given degree of AD pathology may contribute to varying cognitive decline levels in different individuals. Although this phenomenon is attributed to reserve, the biological mechanisms that underpin it remain elusive, which restricts translational medicine research and treatment strategy development. METHODS: Network-based approaches were integrated to identify AD reserve related genes. Then, AD brain transcriptomics data were clustered into co-expression modules, and a Bayesian network was developed using these modules plus AD reserve related phenotypes. The directed acyclic graph suggested that the module was strongly associated with AD reserve. The hub gene of the module of interest was filtered using the topological method. Validation was performed in the multi-AD brain transcriptomic dataset. RESULTS: We revealed that the RALYL (RALY RNA Binding Protein-like) is the hub gene of the module which was highly associated with AD reserve related phenotypes. Pseudo-time projections of RALYL revealed the changes in relative expression drivers in the AD and control subjects over pseudo-time had distinct transcriptional states. Notably, the expression of RALYL decreased with the gradual progression of AD, and this corresponded to MMSE decline. Subjects with AD reserve exhibited significantly higher RALYL expression than those without AD reserve. CONCLUSION: The present study suggests that RALYL may be associated with AD reserve, and it provides novel insights into the mechanisms of AD reserve and highlights the potential role of RALYL in this process.