Metabolic Trans-Omic Analysis Reveals Key Regulatory Disruption of Energy Metabolism in Alzheimer’s Disease

Alzheimer’s disease (AD), a leading cause of dementia, has been recognized as a disease with profound metabolic dysregulation. However, a systems-level view of metabolic regulation across multiple omic modalities in AD remains elusive. Here, we integrated public multi-omic datasets (transcriptome, proteome, and metabolome) from the dorsolateral prefrontal cortex of AD patients and controls. By leveraging existing molecular biological knowledge, we reconstructed a multi-layered metabolic regulatory network to systematically map the interplay between mRNAs, proteins, and metabolites in AD. Our analysis revealed a coordinated downregulation of energy producing pathways, including the TCA cycle, oxidative phosphorylation, and ketone body metabolism, driven by reduced enzyme abundance and inhibitory allosteric effects. In contrast, the glycolysis/gluconeogenesis pathway appeared to be influenced by opposing enzymatic and allosteric regulations. These findings highlight key metabolic dysregulations that may contribute to the bioenergetic deficits in AD pathology.