Plasma proteomic biomarkers as mediators or moderators for the association between poor cardiovascular health and white matter microstructural integrity: The UK Biobank study

The plasma proteome's mediating or moderating roles in the association between poor cardiovascular health (CVH) and brain white matter (WM) microstructural integrity are largely unknown. Data from 3953 UK Biobank participants were used (40-70 years, 2006-2010), with a neuroimaging visit between 2014 and 2021. Poor CVH was determined using Life's Essential 8 (LE8) and reversing standardized z-scores (LE8z _rev). The plasma proteome was examined as a potential mediator or moderator of LE8z _rev's effects on quantitative diffusion-weighted magnetic resonance imaging (dMRI) metrics. LE8z_rev was significantly associated with deteriorated WM microstructural integrity, as reflected by lower tract-averaged fractional anisotropy (dMRI-FAmean), (β ± standared error (SE): -0.00152 ± 0.0003, p < 0.001) and higher tract-averaged orientation dispersion (dMRI-ODmean), (β ± SE:+0.00081 ± 0.00017, p < 0.001). Ten strongly mediating plasma proteins of 1463 were identified, with leptin as the principal driver. Poor CVH is linked to poor WM microstructural integrity measures (lower FAmean and higher ODmean), mostly mediated through leptin. Up to 3953 UK Biobank participants were selected for this study. Poor cardiovascular health (CVH) was determined using Life's Essential 8. The plasma proteome was examined as a potential mediator or moderator of poor CVH's effect on dMRI metrics. Ten plasma proteins were identified with strong mediating effects, with leptin being the principal driver.