Association between metabolomics-based biomarker scores and 10-year cognitive decline in men and women. The Doetinchem Cohort Study

Abstract

BACKGROUND: Metabolomic scores based on age (MetaboAge) and mortality (MetaboHealth) are considered indicators of overall health, but their association with cognition in the general population is unknown. Therefore, the association between MetaboAge/MetaboHealth and level and decline in cognition was studied, as were differences between men and women. METHODS: Data of 2821 participants (50% women, age range 45-75) from the Doetinchem Cohort Study was used. MetaboAge and MetaboHealth were calculated from 1H-NMR metabolomics data at baseline. Cognitive domain scores (memory, flexibility and processing speed) and global cognitive functioning were available over a 10-year period. The association between MetaboAge/MetaboHealth and level of cognitive functioning was studied using linear regressions while for the association between MetaboAge/MetaboHealth and cognitive decline longitudinal linear mixed models were used. Analyses were adjusted for demographics and lifestyle factors. RESULTS: Higher MetaboAge, indicating poorer metabolomic ageing, was only associated with lower levels of processing speed in men. Higher MetaboHealth, indicating poorer immune-metabolic health, was associated with lower levels of cognitive functioning for all three domains and global cognitive functioning in both men and women. Only in men, MetaboHealth was also associated with 10-year decline in flexibility, processing speed and global cognition. Metabolites that contributed to the observed associations were in men mainly markers of protein metabolism, and in women mainly markers of lipid metabolism and inflammatory metabolites. CONCLUSIONS: MetaboHealth, not MetaboAge, was associated with cognitive functioning independent of conventional risk factors. Individual metabolites affect cognitive functioning differently in men and women, suggesting sex-specific pathophysiological pathways underlying cognitive functioning.