Metabolomic signatures of cognitive function in a type 2 Diabetes-Enriched cohort

To understand the relationship between type 2 diabetes (T2D) and risk for developing cognitive impairment, this study is the first to examine association between metabolites measured at mid-life and cognitive performance assessed later in life (8-10 years) in a T2D-enriched cohort. The discovery set included metabolomics from European Americans (EAs; n = 137) and African Americans (AAs; n = 134) from the Diabetes Heart Study (DHS) and the African American-DHS (AA-DHS). The cognitive testing battery included measures of executive function, memory, attention, language, and global cognition. Ancestry-specific linear regression analyses were performed and a false discovery rate (FDR)-corrected p-value was used to assess significance. Overall, fewer significant metabolites were associated with cognitive performance in AAs (n = 19) as compared to EAs (n = 118) suggesting racial differences. There was a positive association between sphingomyelins and cognitive performance, consistent with prior reports. Novel findings implicated partially characterized metabolites linked to oxidative breakdown of bilirubin to multiple cognitive domains suggesting further exploration of this class of metabolites towards improving pathophysiologic understanding and early intervention. Cross-ancestry replication identified four metabolites that generalized to both populations. Replication was performed among additional study participants, i.e. 421 EAs and 167 AAs, followed by a formal meta-analysis. Replication bolstered the association of multiple metabolites with cognitive function. Among these, cortisol was associated in AAs suggesting a link between stress and risk for reduced cognitive function. Further work is needed to provide insight into the pathophysiologic mechanisms and highlight metabolites for inclusion in risk stratification models of cognitive performance.