Multi-omics Integration Implicates RAC/RHO GTPase Cycling and Lipid Metabolic Disruptions in Vascular Cognitive Impairment and Dementia Pathogenesis

Background: Vascular cognitive impairment (VCI) is a major contributor to dementia (20–40% of cases), yet its molecular mechanisms are largely unknown. Traditional single-omics studies, such as those using metabolomics to track biochemical changes, fail to capture the complex, interactive processes driving VCI pathogenesis. Multi-omics integration is an effective, powerful tool that links the genotype to the phenotype, providing the necessary framework to uncover the interconnected molecular pathways underlying VCI. Objectives: This study aimed to move beyond single-layer analyses by applying multi-omics integration to VCI. By simultaneously examining changes at the genomic, epigenomic, transcriptomic, and metabolomic levels, we aimed to unravel VCI-associated molecular disruptions and gain a more complete understanding of the disease mechanisms. Methods: We analyzed Brodmann area 7 brain tissue collected from 19 VCI patients and 21 healthy controls. The analysis involved genomics, epigenomics, transcriptomics, and targeted metabolomics. Data processing consisted of individual (single-layer) analyses followed by integrative computational modeling to define the cross-omics associations and key molecular interactions underlying VCI-related metabolic dysregulation. Results: Multi-omics integration uncovered widespread molecular disruptions in VCI, marked by significant shifts in association networks. Genomic analysis identified the Rac GTPase pathway as a central player, with epigenetic changes found to disrupt the splicing and expression of related genes. Transcriptomic data highlighted disturbances in lipid metabolism, oxidative stress, and GTPase activity, while metabo-epigenomic analysis connected Rac GTPase dysregulation to altered metabolism of diacylglycerol and phosphatidylethanolamine. These results offer fresh insights into the intricate interactions underlying VCI pathophysiology. Conclusion: These results underscore the strength of multi-omics integration in detecting complex molecular interactions and metabolic changes in VCI that are typically missed by single-omics studies. By identifying Rac GTPase-mediated lipid dysregulation, this work offers fresh insights into the pathogenesis of VCI, opening new avenues for biomarker discovery and the development of potential therapeutic strategies. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.