(Poly)phenol and methylxanthine metabolites and their association with cognitive and cardiometabolic health in older people

Dietary (poly)phenols and methylxanthines may help lower the risk of developing neurodegenerative diseases. However, the relationship between (poly)phenols and methylxanthines and age-related cognitive impairment has not been fully explored, in particular (poly)phenol-rich diets using biomarkers. A cross-sectional analysis was conducted on 202 participants aged 60 - 80 diagnosed with mild cognitive impairment (MCI) or two or more cardiometabolic disorders (CMD). The associations between metabolic signature/metabolites, cognition, and cardiometabolic risk were assessed using linear models, adjusted for covariates and multiple testing (FDR < 0.05). The metabolic signature of (poly)phenol-rich diet score (PPS) was linked with Quality of Episodic Memory (QEM), sustained attention, attentional fluctuation and intensity in the subgroups with CMD or MCI (FDR-adjusted p < 0.05). In plasma, 8 (poly)phenol metabolites presented significant inverse associations with MCI diagnosis, with 4-O-caffeoylquinic acid showing the strongest association (odds ratio: 0.84 (95% CI: 0.72, 0.98)). In cerebrospinal fluid (CSF), 6 metabolites were significantly associated with 4 cognitive outcomes, including QEM (FDR-adjusted p < 0.05). As for cardiometabolic outcomes, 5 plasma metabolites were inversely associated with Framingham risk score, while (-)-epicatechin in CSF showed negative associations with LDL-C and TC (FDR-adjusted p < 0.05). Plasma methylxanthine showed favourable associations with cardiometabolic markers, including paraxanthine and HDL-C (stdBeta: 0.17 (0.15, 0.30)), and 3-methylxanthine and HbA1c (stdBeta: -0.25 (-0.43, -0.07)). The PPS signature and (poly)phenol/methylxanthine metabolites from plasma and CSF are significantly associated with favourable cognitive and cardiometabolic outcomes, highlighting the potential role of a (poly)phenol-rich diet, particularly phenolic acids, in promoting cognitive and cardiometabolic health.