Multi-Omics Integration Implicates Rac/Rho GTPase Cycling in Vascular Cognitive Impairment and Dementia Pathogenesis

Background: Vascular cognitive impairment and dementia (VCID) represents a spectrum of cognitive disorders linked to cerebrovascular pathology, yet its molecular underpinnings remain misunderstood. Methods: We conducted a multi-omics analysis of post-mortem brain tissue from the superior parietal lobe (Brodmann area 7) in 19 individuals with neuropathologically confirmed VCID and 21 age-matched controls. Whole genome sequencing, genome-wide DNA methylation profiling, transcriptomic analysis, and metabolomics profiling were performed to identify molecular signatures and integrated pathways involved in VCID pathogenesis. Results: Epigenome-wide association analysis revealed widespread hypermethylation in VCID, with significant enrichment of genes involved in the Rac/Rho GTPase cycle and cytoskeletal remodeling. Transcriptomic analysis confirmed dysregulation of small GTPase signaling, oxidative stress responses, and lipid metabolism. Metabolomic profiling identified altered levels of diacylglycerols (DAGs) and phosphatidylethanolamines (PEs), which showed strengthened associations with Rac/Rho pathway genes in VCID compared to controls. Conclusions: Our integrative multi-omics study identifies the Rac/Rho GTPase cycle as a convergent pathway disrupted at the genomic, epigenomic, transcriptomic, and metabolic levels in VCID. Lipid metabolism, particularly involving DAGs and PEs, emerged as a key downstream effector contributing to VCID. These findings offer mechanistic insights into VCID pathogenesis and suggest lipid signaling pathways as promising therapeutic targets for intervention.