ATP6V1E1 and NDUFB5 identified as potential biomarkers for Alzheimer's disease through integrative analysis.

Alzheimer's disease (AD), a leading cause of dementia, is characterized by mitochondrial dysfunction, including impaired oxidative phosphorylation (OXPHOS), which drives neurodegeneration. This study aimed to identify OXPHOS-related AD biomarkers for early intervention. Integrated analysis of differentially expressed genes from AD temporal lobe and peripheral blood samples, using multivariate logistic regression and LASSO, identified ATP6V1E1 and NDUFB5 as key genes and potential AD risk factors. These genes exhibited strong diagnostic performance (AUC >0.7) and were validated in two independent cohorts. Further western blotting validation using an AD mouse model revealed that both genes were significantly downregulated in the hippocampus. Notably, their expression levels showed significant negative correlations with both Aβ and Tau pathology in AD mouse models. Single-cell RNA-seq analysis indicated their predominant expression in microglia, linking their expression to dysregulated immune cell infiltration. Furthermore, we observed a widespread downregulation of multiple mitochondrial complex I and V-ATPase subunits, indicating a systemic impairment in OXPHOS and lysosomal acidification in AD. This coordinated dysregulation underscores the synergistic dysfunction of mitochondrial and lysosomal systems in AD pathogenesis. This research highlights ATP6V1E1 and NDUFB5 as potential early AD indicators, and provides new insights into both the molecular mechanisms underlying AD pathogenesis and novel therapeutic strategies.