Adaptive Immune Dyshomeostasis as a Mediator of Vascular Cognitive Decline: Unraveling Neurovascular Crosstalk

Vascular cognitive impairment and dementia (VCID), the second most prevalent form of dementia worldwide, arises from cerebrovascular injury and is increasingly recognized as an immune-mediated neurovascular disorder. Mounting evidence implicates dysregulated immune responses-both central and peripheral-as critical drivers of VCID pathogenesis. This review highlights the pivotal roles of microglial activation, astrocytic reactivity, and infiltration of pro-inflammatory T and B cells in disrupting the neurovascular unit (NVU). These processes, mediated by cytokines such as IL-6, IL-17A, and IFN-γ, contribute to the blood-brain barrier (BBB) breakdown, white matter degeneration, and neuronal dysfunction. We further examine how systemic inflammation and comorbidities including hypertension, diabetes, and gut dysbiosis exacerbate immune-neurovascular crosstalk. In light of these insights, we discuss emerging therapeutic strategies aimed at modulating neuroimmune interactions and restoring neurovascular integrity. This integrated perspective provides a foundation for developing precise, immune-targeted interventions in the prevention and treatment of VCID.