Abstract

Vascular cognitive impairment and dementia (VCID) is an age-related neurodegenerative disorder and the second most common cause of dementia. The prevalence of VCID increases with age, and it is a major public health concern due to the lack of effective treatments and the high cost of care. The key pathophysiology of VCID is hypoperfusion caused by vascular dysfunction. Aging and vascular diseases are the most important risk factors for VCID. Cerebrovascular aging leads to the deterioration of vascular function at different levels, particularly in the structural components of the blood-brain barrier (BBB). This disruption impairs the exchange of nutrients and metabolic waste products, contributing to neurodegeneration. White matter injury, characterized by white matter hyperintensities on MRI scans, is also common in VCID and negatively affects cognitive function. Aging-related DNA damage, neuroinflammation, and mitochondrial dysfunction further contribute to the development and progression of VCID.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protecting against oxidative stress and inflammation. NRF2 activation has been shown to have diverse beneficial effects in cerebrovascular components, including endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. In endothelial cells, NRF2 activation improves blood-brain barrier integrity, reduces inflammation, enhances neurovascular coupling, and promotes angiogenesis. In vascular smooth muscle cells, NRF2 activation suppresses abnormal proliferation and migration, thereby maintaining cerebral blood flow. In pericytes, NRF2 activation helps maintain blood-brain barrier integrity and regulates cerebral blood flow. In perivascular macrophages, NRF2 activation modulates the inflammatory response and aids in the clearance of metabolic waste products, such as amyloid beta.

In conclusion, NRF2 activation represents a promising therapeutic target for VCID due to its protective effects in the cerebral vasculature and its potential to mitigate the aging process. Further research, including preclinical and clinical trials, is needed to fully understand the therapeutic potential of NRF2 activators in VCID and to develop effective treatment strategies.