Metabolomic Signatures of Healthy Dietary Patterns Associated With Lower Risk of Age-Related Macular Degeneration

Purpose: The purpose of this study was to evaluate the association of metabolomic signatures reflecting adherence and metabolic response to dietary patterns with prevalence and structural severity of age-related macular degeneration (AMD). Methods: In this cross-sectional study of 1008 eyes from 504 participants, metabolomic profiles in plasma and urine were measured by liquid chromatography-tandem mass spectrometry. Previously derived signatures for eight dietary patterns-including the Alternate Mediterranean diet (AMED), Dietary Approaches to Stop Hypertension (DASH), plant-based diet indices (PDIs), and two mechanism-based diets including Empirical Dietary Inflammatory Pattern (EDIP) and Empirical Dietary Index for Hyperinsulinemia (EDIH)-were evaluated for association with AMD using linear mixed models and Mendelian randomization (MR). Results: Each signature (38-66 metabolites) correlated with its dietary pattern score (Pearson r = 0.16-0.30). Per SD increase in plasma signatures of four healthy dietary patterns (AMED, DASH, PDI, and healthy PDI [hPDI]) were associated with 12% to 16% lower odds of AMD and reduced severity, whereas the unhealthy PDI (uPDI) signature was associated with 13% higher odds and greater severity (false discovery rate [FDR] < 0.05). DASH showed the strongest inverse association with AMD and with atrophy, hyper-reflective foci, and ellipsoid-zone disruption (β = -0.808 to -0.613). Further MR analyses found that genetically instrumented signatures of DASH and Alternate Health Eating Index (AHEI)-2010 were inversely associated with AMD, whereas the EDIP signature was positively associated. Conclusions: Metabolomic signatures of healthy dietary patterns are associated with lower odds and reduced structural severity of AMD. Further longitudinal studies are warranted to validate these findings.