Integrated Multi‐Omics Analysis and Cross‐Model Validation Reveal Mitochondrial Signatures in Alzheimer's Disease

This study's framework begins with large‐scale data integration, leveraging the ROSMAP cohort for multi‐omics discovery (genotyping, DNA methylation, transcriptomics, miRNA) and the ADNI cohort for validation. This data feeds into a comprehensive analytical pipeline where differential expression analysis and an ensemble of 10 machine learning algorithms identify robust mitochondrial biomarkers of AD risk and brain resilience. To explore their biological context, a ceRNA network is constructed, and the key findings are subjected to a rigorous two‐tiered validation: in vivo confirmation of gene expression in an AD mouse model, followed by in vitro functional assessment of mitochondrial health (ROS, membrane potential) in an H 2 O 2 ‐induced oxidative stress model in HT22 cells. This holistic discovery‐to‐validation workflow establishes a robust platform for identifying novel therapeutic targets and advancing our molecular understanding of AD.