Objective <p>To investigate the association between plasma uric acid levels and white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) patients and to explore the potential mediating role of white matter microstructural alterations in the protective effect of plasma uric acid on cognitive function in ALS patients.</p> Methods <p>73 right-handed ALS patients were recruited for this study. Plasma uric acid levels were measured, diffusion tensor imaging scans were performed to assess white matter integrity, and cognition was evaluated using the Edinburgh Cognitive and Behavioral Screen. The relationships among plasma uric acid, white matter integrity, and cognitive function were examined through multivariate linear regression analysis. Additionally, mediation analysis was performed to investigate whether white matter integrity mediated the relationship between uric acid levels and cognitive function.</p> Results <p>The findings revealed a positive correlation between plasma uric acid levels and extensive preservation of white matter microstructure in various regions, including the fornix, cerebellar, internal capsule, frontotemporal and frontooccipital lobe bundles among ALS patients. Mediation analysis indicated that fractional anisotropy in the hippocampal portion of the cingulum fully mediated the effects of plasma uric acid levels on executive function in ALS patients.</p> Interpretation <p>Our results suggested that elevated plasma uric acid may preserve the integrity of white matter microstructure in ALS patients. Furthermore, we have identified evidence supporting the mediating influence of the hippocampal portion of the cingulum in linking plasma uric acid levels to cognitive function among ALS patients.</p>