Integrated bioinformatics and experimental analysis identify apoptosis- and pyroptosis-related hub genes as candidate diagnostic biomarkers in Alzheimer's disease.

Apoptosis and pyroptosis-mediated neuronal death represent major pathogenic mechanisms underlying Alzheimer's disease (AD). Given the potential crosstalk between these two forms of cell death, investigation of a single death pathway may be insufficient to identify robust diagnostic biomarkers for AD. Therefore, this study aimed to explore hub genes involved in both apoptosis and pyroptosis as potential diagnostic biomarkers for AD. First, 23 common cell death-related genes (CDRGs) were identified through bioinformatic analysis. Functional enrichment analyses using GO, KEGG, and GeneMANIA revealed significant associations between AD and biological processes including apoptosis, pyroptosis, and neuronal death. Subsequently, machine learning algorithms combined with ROC curve analysis identified CASP3, IL1B, NLRP3, and PYCARD as candidate biomarkers with potential diagnostic and therapeutic implications for AD. These findings were further validated by the in vitro experiments, which confirmed that the expression levels of these four biomarkers were consistent with the predicted results. Additionally, in patients with AD, CASP3, IL1B, NLRP3, and PYCARD were negatively correlated with macrophages. Collectively, these results suggest that the identified biomarkers may co-regulate apoptosis and pyroptosis through macrophages, thereby contributing to the pathogenesis of AD.