Resolving cognitive heterogeneity in white matter hyperintensities through integrated analyses of microbiome, metabolome, and brain glymphatic function

INTRODUCTION: Individuals with similar white matter hyperintensities (WMH) burden show heterogeneous cognitive outcomes, yet the biological mechanisms underlying this variability remain incompletely understood. METHODS: We integrated 16S rDNA sequencing, untargeted metabolomics, and multi-modal magnetic resonance imaging (MRI) to comprehensively characterize gut microbiome, plasma metabolome, and brain glymphatic function in 56 healthy controls, 40 WMH with normal cognition (WMH-NC), and 49 WMH with cognitive impairment (WMH-CI). RESULTS: Group comparisons revealed differences in six bacterial genera, three plasma metabolites, and five glymphatic markers across three groups, with Acetivibrio, 1,5-naphthalenediamine, beta-uridine, free water fraction within the white matter, and index of diffusivity along the perivascular spaces (ALPS index) showing differences between WMH-CI and WMH-NC. Correlation and mediation analyses demonstrated associations between microbiota and cognition, mediated by tetradecyldiethanolamine and ALPS index. DISCUSSION: These findings provide preliminary insights into plausible microbiota-metabolites-glymphatic function-cognition associations in WMH, potentially informing more targeted interventions for vascular cognitive impairment.