High-resolution metabolomic profiling of Alzheimer's disease in plasma

Ann Clin Transl Neurol. 2020 Jan;7(1):36-45. doi: 10.1002/acn3.50956. Epub 2019 Dec 11.

Abstract

Background: Alzheimer's disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High-resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy.

Methods: Liquid chromatography-mass spectrometry (LC-MS)-based HRM was used to identify plasma and CSF metabolites associated with AD diagnosis and CSF AD biomarkers in two studies of prevalent AD (Study 1: 43 AD cases, 45 mild cognitive impairment [MCI] cases, 41 controls; Study 2: 50 AD cases, 18 controls). AD-associated metabolites were identified using a metabolome-wide association study (MWAS) framework.

Results: An MWAS meta-analysis identified three non-medication AD-associated metabolites in plasma, including elevated levels of glutamine and an unknown halogenated compound and lower levels of piperine, a dietary alkaloid. The non-medication metabolites were correlated with CSF AD biomarkers, and glutamine and the unknown halogenated compound were also detected in CSF. Furthermore, in Study 1, the unknown compound and piperine were altered in MCI patients in the same direction as AD dementia.

Conclusions: In plasma, AD was reproducibly associated with elevated levels of glutamine and a halogen-containing compound and reduced levels of piperine. These findings provide further evidence that exposures and behavior may modify AD risks.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alkaloids / blood
  • Alzheimer Disease / blood*
  • Alzheimer Disease / cerebrospinal fluid
  • Benzodioxoles / blood
  • Biomarkers
  • Chromatography, Liquid
  • Cognitive Dysfunction / blood*
  • Cognitive Dysfunction / cerebrospinal fluid
  • Female
  • Glutamine / blood
  • Humans
  • Male
  • Mass Spectrometry
  • Metabolome*
  • Metabolomics* / methods
  • Middle Aged
  • Piperidines / blood
  • Polyunsaturated Alkamides / blood

Substances

  • Alkaloids
  • Benzodioxoles
  • Biomarkers
  • Piperidines
  • Polyunsaturated Alkamides
  • Glutamine
  • piperine