Untargeted metabolomics reveal dysregulations in sugar, methionine, and tyrosine pathways in the prodromal state of AD

Introduction: Altered metabolism may occur years before clinical manifestations of Alzheimer's disease (AD). We used untargeted metabolomics on the cerebrospinal fluid of patients with mild cognitive impairment (MCI) to uncover metabolomic derangements. Methods: CSF from 92 normal controls and 93 MCI underwent untargeted metabolomics using high-resolution mass spectrometry with liquid chromatography. Partial least squares discriminant analysis was used followed by metabolite annotation and pathway enrichment analysis (PES). Significant features were correlated with disease phenotypes. Results: We identified 294 features differentially expressed between the two groups and 94 were annotated. PES showed that sugar regulation (N-glycan, P =.0007; sialic acid, P =.0014; aminosugars, P =.0042; galactose, P =.0054), methionine regulation (P =.0081), and tyrosine metabolism (P =.019) pathways were differentially activated and significant features within these pathways correlated with multiple disease phenotypes. Conclusion: There is a metabolic signature characterized by impairments in sugars, methionine, and tyrosine regulation in MCI. Targeting these pathways may offer new therapeutic approaches to AD.