Amyloid marker levels and the risk of developing cerebral small vessel disease: A Mendelian randomization study

Previous observational studies have suggested a potential association between amyloid marker levels and the risk of developing cerebral small vessel disease (CSVD), but this relationship remains incompletely understood.

This study was conducted to assess the impact of amyloid marker levels on the risk of developing CSVD via Mendelian randomization (MR) design.

Using the latest genome-wide association study summary statistics for 5 plasma amyloid markers and 4 CSVD traits, a two-sample MR study was conducted to assess the genetic relationship between amyloid marker levels and CSVD risk. Furthermore, reverse MR analysis was utilized to establish the causal relationship between CSVD traits and the levels of the identified plasma amyloid markers to explore potential bidirectional causality.

After FDR correction, greater amyloid-β (Aβ) 42 levels were associated with an increased risk of developing lobar cerebral microbleeds (CMBs) (odds ratio = 2.311, 95% confidence interval 1.403-3.809, p = 0.001, p FDR = 0.040). Potential positive correlations were detected between Aβ₄₀ levels and the risk of developing intracerebral hemorrhage, between Aβ₄₂ levels and the risk of developing all CMBs, and between serum amyloid P component levels and white matter fractional anisotropy status. In reverse MR analysis, no effect of CSVD traits on amyloid marker levels was detected.

Our study suggests potential causal relationships between amyloid marker levels and different CSVD traits. Our results contribute to a greater understanding of the pathophysiology of CSVD, particularly in relation to amyloid deposition.