Epigenetic Insights into Vascular Cognitive Impairment: DNA Methylation in the Human Brain Tissue

Vascular cognitive impairment (VCI) is a common form of dementia that results from vascular damage to the brain, yet the underlying molecular mechanisms remain poorly understood. Epigenetic modifications, particularly DNA methylation, have been implicated in various neurodegenerative diseases, including VCI; however, the details of this association are lacking. This study analyzed Brodmann area 7 tissue samples from 19 individuals with VCI and 21 control subjects. DNA methylation profiles were analyzed using the Illumina EPIC array V2. Integrative bioinformatics approaches, including differentially methylated CpGs (DMCs), differentially methylated regions (DMRs), and gene set enrichment analysis (GSEA), were employed to identify dysregulated pathways associated with VCI. A sex-specific analysis was performed to explore potential differences in methylation patterns between males and females. The analysis revealed significant differential methylation across 3601 CpG sites, with a predominant pattern of hypermethylation (82%) observed in the VCI group. Notably, hypermethylation was detected in key genes related to neurodegeneration and vascular health, such as MTCH2, DPRX, and DENND4A. GSEA identified critical pathways related to neuronal function and vascular health. In sex-specific pathway analysis, vascular regulatory mechanisms were enriched in males and synaptic plasticity together with neuronal development in females. DMRs linked to RAB12 highlighted the role of lysosomal dysfunction in both cognitive and vascular deterioration. Our findings provide novel insights into the epigenetic landscape of VCI, revealing hypermethylation of genes involved in both neuronal and vascular health. The identification of sex-specific differences in epigenetic patterns underscores the need for tailored therapeutic strategies. These results offer potential biomarkers for early diagnosis and new avenues for therapeutic intervention targeting both vascular and neuronal components of VCI.