Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease

Alzheimers Dement. 2023 Dec;19(12):5447-5470. doi: 10.1002/alz.13130. Epub 2023 May 22.

Abstract

Introduction: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest.

Methods: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation.

Results: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10-5 ) and 636 significant protein-biomarker associations (P < 6.07 × 10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers.

Discussion: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD.

Highlights: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.

Keywords: Alzheimer's disease; acylcarnitines; amyloid; biomarkers; carbon metabolism; glucose metabolism; metabolism; metabolomics; multiomics; neurodegeneration; neuroinflammation; proteomics; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism
  • Biomarkers / cerebrospinal fluid
  • Humans
  • Metabolome
  • Peptide Fragments / cerebrospinal fluid
  • Proteome
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Proteome
  • tau Proteins
  • Amyloid
  • Biomarkers
  • Peptide Fragments

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