Vasomechanic treatment is associated with increased efflux of human brain proteins.

An age-related neurovascular impairment in nitric oxide (NO)-mediated vasodilation and reciprocal Piezo1-dependent vascular vasoconstriction may precede the accumulation of soluble brain proteins such as amyloid-β (Aβ) and disruption of brain fluid homeostasis in Alzheimer's disease (AD). Preclinical studies suggest that restoring these pathways can enhance neurofluid transport and improve cognitive outcomes. In this study (EudraCT 2021-000625-27), we investigated the effects of sublingual NO and Piezo1-targeted whole-body vibrations (WBVp) in healthy adults (n = 29) using multimodal neuroimaging and blood biomarker analysis. The combined intervention (NO+WBVp) was associated with correlating changes in brain fluid dynamics and increased blood levels of soluble brain-derived proteins (Aβ40&42, GFAP). These effects increased with age and the magnitude of NO-induced hypotension. The interventions were well tolerated under controlled experimental conditions. Overall, the findings are consistent with transient redistribution of brain-derived proteins toward circulation, suggesting a potential non-invasive approach to increase neurofluidic solute efflux in humans. Pre-specified primary endpoints, changes in circulating brain-derived protein concentrations, brain fluid imaging and brain pulsation measures, were met. Secondary outcomes included physiological analyses.