Mediating Role of Plasma Biomarkers Associated with Metabolic Syndrome in Cognitive Decline Among Older Adults

Metabolic syndrome (MetS), characterized by central obesity, hypertension, hyperglycemia, and dyslipidemia, increases the risk of cardiovascular disease, type 2 diabetes, and cognitive decline in older adults. As the global population continues to age, elucidating the metabolic mechanisms linking MetS to cognitive decline is crucial.

We conducted a cross-sectional study to profile plasma metabolites of 42 MetS patients and 42 healthy controls (median age 69.0 and 68.5 years, respectively) using nuclear magnetic resonance (NMR) prior to mediation analysis. Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA) and Digit Span Tests (Forward and Reverse).

Metabolomic analysis (PLS-DA: Q² = 0.41, R² = 0.50, accuracy 78.3%) identified 13 differentially abundant metabolites, including amino acids (isoleucine, alanine, serine), fatty acid chains, lactate, glycoprotein acetylation (GlycA), acetone, and creatine. Mediation analysis showed that fatty acid chains, GlycA, acetone, lactate, and isoleucine exhibited significant competitive mediation effects between MetS and delayed recall function. Furthermore, lactate levels fully mediated the effects between MetS and attention.

Metabolite biomarkers associated with cognitive decline in older adults with MetS were identified, with lactate, isoleucine, GlycA, acetone, and fatty acid being associated with better delayed recall performance, whereas elevated lactate levels were associated with poorer attention. Longitudinal and interventional studies are needed to confirm these pathways and clarify their implications for cognitive health in this population.