Glucometabolic-Related Genes as Diagnostic Biomarkers and Therapeutic Targets for Alzheimer's Disease and Type 2 Diabetes Mellitus: A Bioinformatics Analysis.

Abstract

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two widespread chronic disorders characterized by shared risk factors and molecular pathways. Glucose metabolism, pivotal for cellular homeostasis and energy supply, plays a critical role in these diseases. Its disturbance has been linked to the pathogenesis of both AD and T2DM. However, a comprehensive investigation into the specific roles of glucometabolic genes in the onset and progression of AD and T2DM has yet to be conducted. By analyzing microarray datasets from the Gene Expression Omnibus (GEO) repository, we identified differentially expressed glucometabolic genes (DEGs) in AD and T2DM cohorts. A range of bioinformatics tools were employed for functional annotation, pathway enrichment, protein interaction network construction, module analysis, ROC curve assessment, correlation matrix construction, gene set enrichment analysis, and gene-drug interaction mapping of these DEGs. Key genes were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) in AD and T2DM murine models. Our investigation identified 41 glucometabolic-related DEGs, with six prominent genes (G6PD, PKM, ENO3, PFKL, PGD, and TALDO1) being common in both AD and T2DM cohorts. These genes play crucial roles in metabolic pathways including glycolysis, pentose phosphate pathway, and amino sugar metabolism. Their diagnostic potential was highlighted by area under curve (AUC) values exceeding 0.6 for AD and 0.8 for T2DM. Further analysis explored the interactions, pathway enrichments, regulatory mechanisms, and potential drug interactions of these key genes. In the AD murine model, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed significant upregulation of G6pd, Eno3, and Taldo1. Similarly, in the T2DM murine model, elevated expression levels of G6pd, Pfkl, Eno3, and Pgd were observed. Our rigorous research sheds light on the molecular interconnections between AD and T2DM from a glucometabolic perspective, revealing new opportunities for pharmacological innovation and therapeutic approaches. This study appears to be the first to extensively investigate glucometabolic-associated DEGs and key genes in both AD and T2DM, utilizing multiple datasets. These insights are set to enhance our understanding of the complex pathophysiology underlying these widespread chronic diseases.