Enhanced metabolic flexibility links Mediterranean diet with cognition: interim findings from a randomized controlled...

Metabolomics contributes to the understanding of mechanisms by which dietary interventions can minimize the progression of mild cognitive impairment (MCI) to dementia. In this study, changes in metabolomics profiles were analyzed to assess the effects of a 24-week intervention with a Mediterranean diet (MD), with and without probiotics, and a low-fat diet (according to the World Health Organization recommendations) in 47 older adults (aged ≥60 years, 42.6% women) with MCI. The plasma metabolome was analyzed using a quantitative LC-MS/MS targeted assay to assess metabolite changes derived from dietary intervention. Multivariate methods were employed to assess the impact of diets on the plasma metabolome, as well as the associations between the changes in metabolite profiles and cognitive evaluation scores (assessed through ADAS-Cog-11 and a complete neuropsychological test battery). Our results showed that the MD increased the levels of acetoacetic acid and various metabolites linked to the tricarboxylic acid (TCA) cycle and decreased the levels of branched-chain amino acids (BCAAs), particularly isoleucine. Increases in alpha-ketoglutarate, alpha-ketoisovalerate, and 2-oxocaproate, as well as decreases in beta-alanine, L-carnitine, and alpha-aminobutyric acid concentrations, were associated with improved cognitive scores. The MD, but not the low-fat diet, promoted ketone body production and increased the availability of TCA cycle intermediates, suggesting an increase in metabolic flexibility in older adults with MCI. Targeted dietary and/or pharmacological strategies aimed at enhancing metabolic flexibility may open new avenues for preventing the progression of MCI. This study is registered with ClinicalTrials.gov (NCT05029765).