Diet‐Related Metabolites Associated with Cognitive Decline Revealed by Untargeted Metabolomics in a Prospective Cohort

Abstract

Scope Untargeted metabolomics may reveal preventive targets in cognitive aging, including within the food metabolome. Methods and results A case‐control study nested in the prospective Three‐City study includes participants aged ≥65 years and initially free of dementia. A total of 209 cases of cognitive decline and 209 controls (matched for age, gender, education) with slower cognitive decline over up to 12 years are contrasted. Using untargeted metabolomics and bootstrap‐enhanced penalized regression, a baseline serum signature of 22 metabolites associated with subsequent cognitive decline is identified. The signature includes three coffee metabolites, a biomarker of citrus intake, a cocoa metabolite, two metabolites putatively derived from fish and wine, three medium‐chain acylcarnitines, glycodeoxycholic acid, lysoPC(18:3), trimethyllysine, glucose, cortisol, creatinine, and arginine. Adding the 22 metabolites to a reference predictive model for cognitive decline (conditioned on age, gender, education and including ApoE‐ε4, diabetes, BMI, and number of medications) substantially increases the predictive performance: cross‐validated Area Under the Receiver Operating Curve = 75% [95% CI 70–80%] compared to 62% [95% CI 56–67%]. Conclusions The untargeted metabolomics study supports a protective role of specific foods (e.g., coffee, cocoa, fish) and various alterations in the endogenous metabolism responsive to diet in cognitive aging.

Early signature in the blood lipidome associated with subsequent cognitive decline in the elderly: A case-control analysis nested within the Three-City cohort study

“…In 2016, an ancillary study was initiated in 3C to investigate metabolomics and lipidomics profiles in relation to subsequent trajectories of cognitive decline [32] . This omics sub-study was based on a case-control study on cognitive decline, nested within the Bordeaux study center.…”

Mechanistic Insights into Alzheimer’s Disease Unveiled through the Investigation of Disturbances in Central Metabolites and Metabolic Pathways

“…In another cohort, the analysis of serum samples evidenced similar alterations in metabolites related to oxidative stress, deficiencies in energy metabolism, and vascular risk factors [ 57 ]. Furthermore, the authors also found increased serum levels of proline betaine in AD patients, which is a marker of citrus consumption that has been recently validated in a prospective study on cognitive decline [ 69 ]. In this line, the analysis of brain tissue demonstrated that AD pathogenesis could be associated with dysregulated transmethylation and polyamine metabolism, abnormalities in neurotransmission, and impaired urea cycle and glutathione synthesis [ 58 ].…”

Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression: The ACTION Biomarker Study

“…In the current study the current study we find associations with childhood aggression for ethanolamine, involved in the synthesis of phospholipids, N6-N6-N6-trimethyl-L-lysine, involved in oxidation of fatty acids, and glyceric acid, involved in glycerolipid metabolism. Previously, glyceric acid was included in a panel capable of discriminating between patients with schizophrenia and controls with an AUC of 0.94 (66), lower serum levels of ethanolamine were observed in APD patients as compared to controls (50), lower CSF levels of ethanolamine were reported in MDD patients as compared to controls and associated to depression severity and increased somatic anxiety symptoms in MDD patients (67), in addition, serum levels of N6-N6-N6-trimethyl-L-lysine have been associated with cognitive decline (68).…”