Inflammaging and neurovascular unit dysfunction in cognitive ageing: mechanisms, biomarkers, and therapeutic...

Age-related cognitive decline is increasingly recognised as arising from interacting immune and neurovascular vulnerabilities rather than from isolated insults. In this Review, we synthesise current human and mechanistic evidence within a convergence framework in which inflammaging and neurovascular unit (NVU) dysfunction are conceptualised as a feedback-coupled system. Persistent immune remodelling may promote endothelial activation, redox imbalance, pericyte-astrocyte support failure, microglial priming, and impaired neurovascular coupling, thereby reducing cerebrovascular reserve and destabilising blood-brain barrier (BBB) selectivity and transport. Conversely, emerging NVU dysfunction may amplify neuroimmune signalling and increase the susceptibility of white matter and synapses to late-life injury. We organise the literature around three mechanistic interfaces-immune-endothelium, glia-vascular, and flow-metabolic-and assess how this framework may clarify biomarker stratification, mechanism-aligned endpoint selection, and heterogeneity of intervention responses. Current evidence is strongest for integrative plausibility across inflammatory, vascular, and cognitive domains, but remains more limited for temporal ordering, effect modification, and reversibility in humans. We highlight key uncertainties, including peripheral-to-central signalling, harmonisation of BBB metrics, and heterogeneity across mixed late-life pathologies, and assess the therapeutic implications of immune- and NVU-directed strategies.