Abstract
Cerebral small vessel disease (CSVD) burden and plasma biomarkers are both critically associated with white matter (WM) microstructural damage and cognitive decline. However, whether these factors interact synergistically to exacerbate brain degeneration and cognitive decline remains unclear. We included 375 Chinese participants from the Aging cohort at Nanjing Drum Tower Hospital: 144 with no CSVD, 103 with mild CSVD (CSVD-I) and 128 with moderate to severe CSVD (CSVD-II). All participants underwent comprehensive cognitive assessment, plasma biomarker quantification and MRI scanning. Diffusion tensor imaging was used to evaluate WM microstructure. Interaction effects between CSVD burden and plasma biomarkers were analysed, and path analyses were performed to explore how two factors synergistically influence WM tracts and cognitive impairment. We found significant interactions between phosphorylated tau 181 (p-tau(181)) and CSVD burden on the integrity of multiple WM tracts (P (FDR) < 0.05). The CSVD-II showed the strongest effect of p-tau(181) on neurofilament light, as well as an indirect effect of the cingulum mediating the relationship between p-tau(181) and cognition [Δ IE¯ = -0.108, 90% CI = (-0.25, -0.0302)]. Our findings suggest that vascular and molecular pathologies synergistically contribute to WM integrity damage and cognitive impairment. Targeting both vascular and molecular factors may be crucial for developing effective interventions to mitigate cognitive decline in the elderly population.