Identification of NDUFV2, NDUFS7, OPA1, and NDUFA1 as biomarkers for Alzheimer's disease: Insights from oxidative stress and mitochondrial dysfunction in the hippocampus

Background Alzheimer's disease (AD) is characterized by amyloid-β deposits, neurofibrillary tangles, and hippocampal neurodegeneration, with oxidative stress and mitochondrial dysfunction playing critical roles in its pathogenesis. Identifying hub genes associated with these processes could advance biomarker discovery and therapeutic strategies. Objective This study aimed to identify key oxidative stress- and mitochondrial dysfunction-related genes in the AD hippocampus, evaluate their diagnostic potential, and explore therapeutic agents targeting these genes. Methods We analyzed datasets GSE48350 and GSE5281, encompassing 56 controls and 29 AD patients. Weighted gene co-expression network analysis (WGCNA) selected genes with significance (adjusted p -value < 0.05 and |logFC| ≥ 0.5). Further studies involved immune cell infiltration, Gene set enrichment analysis (GSEA), and intersecting differentially expressed genes (DEGs) with oxidative stress-related genes (ORGs) and mitochondrial dysfunction-related genes (MDRGs). Functional enrichment and Protein-protein interaction (PPI) analyses were conducted. Experimental validation was done in AD mouse models, and diagnostic potential was tested using datasets GSE28146 and GSE29652. Therapeutic drugs were predicted based on hub genes. Results AD showed altered immune cell expression. GSEA linked DEGs to nervous system processes and neurotransmitters. 194 oxidative stress-related DEGs were enriched in neuronal death and mitochondrial processes. PPI analysis identified 24 DEGs related to both oxidative stress and mitochondrial dysfunction (DEO-MDRGs), with diagnostic potential (AUC > 0.5). LASSO regression selected four DEO-MDRGs: NDUFV2, NDUFS7, OPA1, and NDUFA1. Their protein levels were reduced in AD mice with decreased mitochondrial function. These genes showed good diagnostic performance. Potential drugs, like ME-344 and metformin hydrochloride, may be useful in AD treatment. Conclusions NDUFV2, NDUFS7, OPA1, and NDUFA1 can serve as biomarkers for AD diagnosis.