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

Authors

• Milda Milcuite
• Sangeetha Vishweswaraiah, Corewell Health East
• Nadia Ashrafi, Corewell Health East
• Romana Mimi, Corewell Health East
• Nazia Saiyed, Corewell Health East
• Abdullah Khalid, Corewell Health East
• Ceyda Buyuker
• Boran Aksakal
• Lorena Ferreira Gomes, Corewell Health East Resident
• Migle Gabrielaite
• Ingrida Olendraite
• Vilija Lomeikaite
• Juozas Gordevicius
• Ali Yilmaz, Corewell Health East
• Stewart Graham, Corewell Health East

Document Type

Conference Proceeding

Publication Date

5-2026

Publication Title

Physiology

Abstract

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.

Volume

41

Issue

Suppl 1

Recommended Citation

Milciute M, Vishwewaraiah S, Ashrafi N, Mimi R, Saiyed N, Khalid A, et al. [Ferreira Gomes L, Yilmaz A, Graham S]. Multi-omics integration implicates RAC/RHO GTPase cycling and lipid metabolic disruptions in vascular cognitive impairment and dementia pathogenesis. Physiology (Bethesda). 2026 May;41(Suppl 1). doi:10.1152/physiol.2026.41.S1.2299690

Comments

American Physiology Summit, April 23-26, 2026, Minneapolis, MN

DOI

10.1152/physiol.2026.41.S1.2299690