Deep White-Matter Pathways Mediate the Link Between Docosahexaenoic Acid (DHA) Status and Cognitive Performance in Adolescence

Abstract

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid enriched in neuronal membranes and myelin and associated with cognitive performance. However, nutritional interventions show inconsistent cognitive effects, partly due to limited knowledge of the neural pathways linking DHA status to human cognition during sensitive periods of white-matter maturation, such as adolescence. We addressed this gap by studying 99 adolescents drawn from both extremes of performance on a national scholastic examination. Participants completed assessments of scholastic achievement (SA) and intellectual ability (IA), provided erythrocyte DHA samples, and underwent multimodal MRI, including diffusion, T1-weighted, and T2-weighted imaging. Independent component analysis and Bayesian multivariate LASSO models identified brain components jointly associated with DHA and cognition. Across four MRI modalities, a single deep white-matter component consistently emerged as the strongest shared pathway linking DHA with cognition. Tract-resolved analyses highlighted predominant contributions from the fornix and thalamus-temporal fasciculus, with additional subcortical and cortical involvement. In joint models, these components predicted SA and IA after accounting for DHA and other fatty acids, consistent with an indirect, mediation-like pathway. These findings move beyond DHA-behavior correlations by identifying specific neuroanatomical pathways through which a modifiable dietary factor relates to adolescent learning and intellectual performance, offering mechanistic insight relevant to neuroscience, nutrition, and education. Significance StatementAdolescence is a sensitive period for the maturation of white-matter pathways that support learning and reasoning. Docosahexaenoic acid (DHA), an essential dietary fatty acid enriched in neuronal membranes and myelin, has been linked to cognitive performance, yet the neural mechanisms underlying this association remain unclear. Using multimodal MRI and Bayesian multivariate modeling in adolescents with high or low scholastic performance, identify a specific deep white-matter pathway--centered on the fornix and the thalamus-temporal fasciculus--as the principal route connecting DHA status with scholastic achievement and intellectual ability. Additional subcortical and cortical contributions reveal a coordinated system-level architecture. These findings move beyond correlations by providing mechanistic insight into how a modifiable nutritional factor relates to cognitive development, with implications for neuroscience, public health, and education.