Disparate plasma metabolomic profiles in late-life depression and amnestic mild cognitive impairment: A 1H NMR metabolomics study

Objective This study aims to delineate the plasma metabolic signatures of late-life depression (LLD) and amnestic mild cognitive impairment (aMCI), two prodromal populations at high risk for dementia, and to identify candidate biomarkers for early intervention. Methods Plasma samples from 53 elderly participants (11 LLD, 26 aMCI, 16 healthy controls) were analyzed by 1 H-nuclear magnetic resonance ( 1 H NMR) metabolomics. The differential metabolites were screened and correlated with neurocognitive scores, and then the diagnostic efficacy was evaluated by the receiver operating characteristic (ROC) curve. Finally, Mendelian randomization was used to verify the potential causal relationship between these candidate biomarkers and dementia. Results Both LLD and aMCI displayed marked metabolic perturbations, primarily affecting glycolysis/gluconeogenesis, galactose metabolism, and arginine biosynthesis. Scyllo-inositol was significantly elevated in LLD and reduced in aMCI. It discriminated LLD, aMCI, and healthy controls, and correlated with neurocognitive tests scores. Combination of scyllo-inositol with memory scales yielded promising diagnostic performance. Its AUC was 0.920 (95%CI: 0.808–1.000) for distinguishing LLD from HC, and 0.950 (95%CI: 0.892–1.000) for distinguishing aMCI from HC. There is a potential causal relationship between scyllo-inositol and dementia. Conclusion These findings elucidate the metabolic link between LLD and aMCI and support a preliminary model combining plasma metabolites with cognitive testing for early identification and precise intervention in high-risk populations for dementia.