Comprehensive Analysis of Metabolites in Postmortem Brains of Patients with Alzheimer’s Disease

Background: Disturbed metabolism has been proposed as being involved in the pathogenesis of Alzheimer’s disease (AD), and more evidence from human AD brains is required. Objective: In this study, we attempted to identify or confirm modulations in the levels of metabolites associated with AD in postmortem AD brains. Methods: We performed metabolomics analyses using a gas chromatography mass spectrometry system in postmortem brains of patients with confirmed AD, patients with CERAD score B, and control subjects. Results: Impaired phosphorylation of glucose and elevation of several tricarboxylic acid (TCA) metabolites, except citrate, were observed and the degree of impaired phosphorylation and elevation in the levels of the TCA cycle metabolites were negatively and positively correlated, respectively, with the clinical phenotypes of AD. The levels of uronic acid pathway metabolites were modulated in AD and correlated positively with the amyloid-β content. The associations of nucleic acid synthesis and amino acid metabolites with AD depended on the kinds of metabolites; in particular, the contents of ribose 5-phosphate, serine and glycine were negatively correlated, while those of ureidosuccinic acid and indole-3-acetic acid were positively modulated in AD. Comprehensive statistical analyses suggested that alterations in the inositol pathway were most closely associated with AD. Conclusions: The present study revealed many novel associations between metabolites and AD, suggesting that some of these might serve as novel potential therapeutic targets for AD.