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

Abstract

Alzheimers 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 potential interplay among mRNAs, proteins, and metabolites in AD. Our analysis revealed a putative 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 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.