Untargeted metabolomics reveals sugar and homocysteine dysregulations in prodromal AD

Introduction Altered metabolism may occur early in Alzheimer’s disease (AD). We used untargeted high-resolution metabolomics in the cerebrospinal fluid (CSF) in mild cognitive impairment (MCI) to identify these alterations. 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 using spearman correlation. Results We identified 294 features differentially expressed between the 2 groups and 94 were annotated. PES showed that pathways related to sugar regulation (N-Glycan, p =0.0007; sialic acid, p =0.0014; Aminosugars, p =0.0042; galactose, p =0.0054) homocysteine regulation ( p =0.0081) were differentially activated and significant features within these pathways correlated with disease phenotypes. Conclusion We identified a metabolic signature characterized by impairments in sugar and homocysteine regulation in prodromal AD. Targeting these changes may offer new therapeutic approaches to AD Research in Context Systematic review: The authors searched PUBMED and Google Scholar for previous reports of metabolomics and Alzheimer’s disease. Search Terms included: mild cognitive impairment, Alzheimer’s disease “AND” metabolism, metabolomics. This search identified multiple small studies that have conducted untargeted metabolomics in AD. This search resulted in the following findings: Prior studies have either included small samples, used targeted approaches, or focused on plasma profiling. In this study, we conducted a case-control untargeted high resolution metabolomic study on the CSF of a larger sample of normal cognition and mild cognitive impairment. Interpretation: We discovered that pathways in sugar metabolism, homocysteine and tyrosine were dysregulated in AD. Further, features that were significantly different between MCI and normal cognition had different patterns of association with cognitive, neuroimaging and Amyloid and tau biomarkers. Future direction: These pathways offer new potential targets for AD Highlights Metabolic signature is detectable in prodromal AD Multiple sugar metabolism pathways are dysregulated in prodromal AD. S-adenosylmethionine is under- and S-adenosylhomocysteine is overexpressed in AD