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BACKGROUND: Emerging evidence highlights that diet dynamically shapes the gut microbiome, which in turn influences cognitive function through bidirectional gut-brain communication, offering a promising target for mitigating cognitive decline and neurodegenerative disorders. While the Mediterranean diet (MedDiet) is a well-established dietary pattern with demonstrated neuroprotective benefits, the interplay between MedDiet adherence, gut microbiota, and longitudinal cognitive trajectories remains poorly understood. We aimed to identify a gut microbial signature of the MedDiet adherence and prospectively examine the associations of MedDiet adherence and MedDiet gut microbial signature (MedDiet-GMS) with cognitive changes over time in older adults at high risk of cognitive decline.METHODS: This study included 746 participants (mean age 65 ± 5 years, 48% women) with overweight/obesity and metabolic syndrome. Adherence to the MedDiet was assessed using a validated 14-item Mediterranean Diet Adherence Screener (MEDAS). Baseline gut microbiota composition was profiled via 16S rRNA sequencing. Cognitive function was evaluated at baseline, 2, 4, and 6 years using a comprehensive neuropsychological battery. Elastic net regressions were applied to derive a MedDiet-GMS, and linear mixed models were used to assess associations of both MEDAS and MedDiet-GMS with trajectories of cognitive function, adjusting for potential confounders.RESULTS: Higher adherence to the MedDiet was associated with greater gut microbial diversity (p < 0.05) and distinct microbial composition (PERMANOVA, p = 0.001). The MedDiet-GMS comprised 20 taxa, including short-chain fatty acid-producers (e.g., Barnesiella, Butyricicoccus) positively weighted and pro-inflammatory taxa (e.g., Eggerthella) negatively weighted. Both higher MEDAS scores (p = 0.007) and MedDiet-GMS (p = 0.036) were independently associated with slower global cognitive decline. The MedDiet-GMS was additionally linked to preserved executive function (p = 0.049), while MEDAS was associated with attenuated general cognitive decline (p = 0.028). Eggerthella, inversely associated with MedDiet adherence, was linked to greater executive function decline (FDR < 0.05).CONCLUSIONS: Greater adherence to the MedDiet was associated with a favorable gut microbiota profile and slower cognitive decline over 6-year of follow-up. A microbiome-derived signature of MedDiet adherence was prospectively associated with favorable cognitive trajectories in older adults at risk of cognitive decline. External validation and experimental research are warranted to translate these findings into targeted microbiome-based dietary interventions for healthy cognitive aging.