Identification of Oxidative Stress-related Genes Differentially Expressed in Alzheimer's Disease and Construction of a Hub Gene-based Diagnostic Model

Alzheimer's disease (AD) is the most prevalent dementia disorder globally, and there are still no effective interventions for slowing or stopping the underlying pathogenic mechanisms. There is strong evidence implicating neural oxidative stress (OS) and ensuing neuroinflammation in the progressive neurodegeneration observed in the AD brain both during and prior to symptom emergence. Thus, OS-related biomarkers may be valuable for prognosis and provide clues to therapeutic targets during the early presymptomatic phase. In the current study, we gathered brain RNA-seq data of AD patients and matched controls from the Gene Expression Omnibus (GEO) to identify differentially expressed OS-related genes (OSRGs). These OSRGs were analyzed for cellular functions using the Gene Ontology (GO) database and used to construct a weighted gene co-expression network (WGCN) and protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curves were then constructed to identify network hub genes. A diagnostic model was established based on these hub genes using Least Absolute Shrinkage and Selection Operator (LASSO) and ROC analyses. Immune-related functions were examined by assessing correlations between hub gene expression and immune cell brain infiltration scores. Further, target drugs were predicted using the Drug-Gene Interaction database, while regulatory miRNAs and transcription factors were predicted using miRNet. In total, 156 candidate genes were identified among 11046 differentially expressed genes, 7098 genes in WGCN modules, and 446 OSRGs, and 5 hub genes (MAPK9, FOXO1, BCL2, ETS1, and SP1) were identified by ROC curve analyses. These hub genes were enriched in GO annotations "Alzheimer's disease pathway," "Parkinson's Disease," "Ribosome," and "Chronic myeloid leukemia." In addition, 78 drugs were predicted to target FOXO1, SP1, MAPK9, and BCL2, including fluorouracil, cyclophosphamide, and epirubicin. A hub gene-miRNA regulatory network with 43 miRNAs and hub gene-transcription factor (TF) network with 36 TFs were also generated. These hub genes may serve as biomarkers for AD diagnosis and provide clues to novel potential treatment targets.