Background <p>Observational studies have linked high adherence to the “Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay” (MIND) diet to improved cognitive functions in older adults. The underlying peripheral and central mechanisms of this association remain poorly understood, although multiple nutrients in the MIND diet are known for their anti-inflammatory effects. Therefore, we explored the cross-sectional relation between MIND diet adherence (Dutch version), systemic inflammation, neuroinflammation, and cognitive functioning in older adults. In addition, we examined the role of intestinal barrier permeability in MIND diet associations with (neuro)inflammation.</p> Methods <p>We included 88 older adults (60–75 year) at risk of cognitive decline. MIND-NL diet adherence was assessed using a food frequency questionnaire. Systemic inflammation (C-reactive protein levels, white blood cell-counts and neutrophil-to-lymphocyte ratio) and intestinal barrier permeability (lipopolysaccharide-binding protein, zonulin, and lipopolysaccharide) markers were measured in blood. Neuroinflammation-associated metabolites (myo-inositol, choline and creatine) were measured in the dorsolateral prefrontal cortex with proton magnetic resonance spectroscopy (¹H-MRS). Cognitive functioning was assessed with a neuropsychological test battery.</p> Results <p>Linear models showed that both MIND diet adherence and systemic inflammation did not predict neuroinflammation or cognition independently. However, MIND diet adherence significantly moderated the relation between systemic inflammation and neuroinflammation (β=-0.22, <i>p</i> = 0.04) as well as between systemic inflammation and cognition (β = 0.22, <i>p</i> = 0.02). Specifically, in individuals with lower MIND diet adherence (identified as scores ≤ 7), systemic inflammation was positively related to neuroinflammation, and negatively to cognition. Similarly, MIND diet adherence significantly moderated the relation between intestinal barrier permeability and neuroinflammation (β=-0.28, <i>p</i> = 0.05). Finally, within participants with lower MIND diet adherence (median split at ≤ 8.75), systemic inflammation mediated the relation between the intestinal barrier permeability and neuroinflammation (path coefficient = 0.427 [0.072; 0.891], <i>p</i> = 0.04).</p> Conclusion <p>Our findings show that MIND diet adherence modulates inflammation-brain relationships in aging, with detrimental associations between systemic inflammation and both neuroinflammation and cognitive functioning observed only in individuals with lower adherence. Moreover, MIND diet adherence similarly modulates the systemic inflammation-mediated relationship between intestinal barrier permeability and neuroinflammation. These findings should be confirmed in randomized controlled trials.</p>