# Synergistic effects of cerebral small vessel disease burden and plasma phosphorylated tau 181 on white matter microstructure and cognition in a Chinese cohort

## TL;DR

This study shows that brain vessel disease and a specific brain protein marker work together to worsen brain structure and thinking in older adults.

## Contribution

The study reveals a synergistic interaction between cerebral small vessel disease and plasma p-tau181 in affecting white matter and cognition.

## Key findings

- p-tau181 and CSVD burden interact to damage multiple white matter tracts.
- Higher CSVD severity amplifies the effect of p-tau181 on brain markers of degeneration.
- The cingulum tract mediates the relationship between p-tau181 and cognitive decline.

## 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-tau181) and CSVD burden on the integrity of multiple WM tracts (PFDR < 0.05). The CSVD-II showed the strongest effect of p-tau181 on neurofilament light, as well as an indirect effect of the cingulum mediating the relationship between p-tau181 and cognition [ΔIE¯ = −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.

Xu et al. report that cerebral small vessel disease burden and plasma p-tau181 synergistically affect white matter microstructure and cognition in a Chinese cohort. The findings highlight a synergistic interaction between vascular and tau pathologies, underscoring the importance of integrated strategies for mitigating cognitive decline.

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