One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: Homocysteine and beyond

Loïc Dayon, Seu Ping Guiraud, John Corthésy, Laeticia Da Silva, Eugenia Migliavacca, Domile Tautvydaite, Aikaterini Oikonomidi, Barbara Moullet, Hugues Henry, Sylviane Métairon, Julien Marquis, Patrick Descombes, Sebastiano Collino, François Pierre J. Martin, Ivan Montoliu, Martin Kussmann, Jérôme Wojcik, Gene Bowman, Julius Popp

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Abstract

Background: Hyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur-containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one-carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults. Methods: Cross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one-carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/β-Amyloid 1-42 peptide chain [Aβ1-42] >0.0779) to establish a reference benchmark. Two other LASSO-determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) ϵ4 carrier status. Results: The diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Aβ1-42, tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine, glycine, methionine, SAH, SAM, serine, cysteine, and Hcy and reached a diagnostic accuracy of 87.5%. CSF SAH and 5-MTHF were associated with CSF tau and p-tau181. Plasma one-carbon metabolites were able to diagnose subjects with a positive CSF profile of AD pathology in APOE ϵ4 carriers. Conclusions: We observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p-tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE ϵ4 carriers.

Original languageEnglish (US)
Article number43
JournalAlzheimer's Research and Therapy
Volume9
Issue number1
DOIs
Publication statusPublished - Jun 17 2017
Externally publishedYes

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Keywords

  • Alzheimer's disease
  • Cognition
  • CSF
  • Homocysteine
  • Metabolomics
  • One-carbon metabolism
  • S-adenosyl-L-homocysteine
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Dayon, L., Guiraud, S. P., Corthésy, J., Da Silva, L., Migliavacca, E., Tautvydaite, D., ... Popp, J. (2017). One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: Homocysteine and beyond. Alzheimer's Research and Therapy, 9(1), [43]. https://doi.org/10.1186/s13195-017-0270-x