Molecular pathways in vascular cognitive impairment and dementia: focus on synaptic plasticity and epigenetic modifications

Background: Vascular cognitive impairment (VCI) is a group of cognitive disorders caused by cerebrovascular disease and is the second leading cause of dementia. VCI prevalence has significantly increased over the past decade. However, the molecular mechanisms underlying VCI remain unclear. Objective: This review summarizes recent reports on the critical roles of hippocampal synaptic plasticity and epigenetic changes in VCI and vascular dementia (VaD) by incorporating findings from neuroimaging and molecular biology. Methods: We reviewed studies employing molecular, electrophysiological, and neuroimaging approaches, conducted over the last two decades. Key targets of investigation included cerebral blood flow regulation, synaptic transmission, and epigenetic mechanisms such as DNA methylation, histone modification, and noncoding RNA regulation. Results: Growing evidence suggests that chronic cerebral hypoperfusion and microvascular injury cause deficits in hippocampal synaptic plasticity, leading to long-term potentiation and memory formation deficits. Aberrant epigenetic changes, such as dysregulated DNA methylation, histone acetylation, and miRNA expression, contribute to neuroinflammatory and neurodegenerative processes. Electroencephalography and functional magnetic resonance imaging studies reflect changes in neural connectivity and network dynamics, and molecular imaging provides molecular-level evidence of these changes. Conclusion: VCI is caused by the complex interaction of vascular dysfunction, synaptic dysregulation, and epigenetic modification. Identification of these convergent mechanisms may pave the way for new diagnostic biomarkers and therapeutic targets. Future studies on neuroimaging, molecular profiling, and epigenetic modifications could facilitate the early detection and precision-based treatment of VCI and VaD.