Biological brain aging, cognitive-motor decline and vascular risk: a multivariate imaging analysis of 40,579 individuals

Introduction Age-related declines in cognitive and motor functions show highly variable trajectories. To better understand the underlying mechanisms, we investigated multivariate associative effects between modifiable vascular risk factors, biological brain aging, cognitive, and motor performance in 40,579 individuals from the population-based UK Biobank and Hamburg City Health Study. Methods We employed partial least squares correlation analysis (PLS) to model associations between multi-domain cognitive and motor test scores and three distinct MRI-derived markers of biological brain aging: relative brain age (from morphometric brain imaging), white matter hyperintensity load, and peak width of skeletonized mean diffusivity. Furthermore, we conducted mediation analyses to assess if these markers mediate the impact of vascular risk on functional decline. Results PLS identified a single dominant latent dimension explaining 94.7% of the shared variance between neuroimaging and behavior. This dimension linked higher biological brain aging markers – with relative brain age showing the strongest contribution – to poorer cognitive and motor performance, particularly in executive function and processing speed. Mediation analysis revealed that biological brain aging acts as a partial mediator for the negative effects of blood pressure, glucose, waist-hip ratio, and smoking load on cognitive and motor function. Notably, this mediating effect was not observed for cholesterol levels. These results were consistent across both cohorts. Discussion Our study illustrates the associative interplay between vascular health, biological brain aging, and cognitive and motor performance, emphasizing the need for preventive strategies to maintain late-life independence in aging populations.