Table 3.

Summary of metabolomic studies conducted in AD patients.

Analytical platform	Samples	Findings	References
LC-ECA Focused on neurotransmitter and oxidative stress pathways	Post-mortem ventricular CSF from 15 AD and 15 CN	Norepinephrine (NE) levels lower in AD vs. CN NE, methionine, and alpha-tocopherol negatively correlated with tangle formation and/or amyloid deposition 5-hydroxytryptophan and tyramine positively correlated with tangle formation and/or amyloid deposition	[42]
GC-MS and LC-MS/MS for broad profiling SPE-LC-MS/MS for catecholamine and steroids	CSF from 79 AD (53 mild and 26 moderate) and 51 CN	Greater metabolic changes in female vs. male AD Greater metabolic changes in mild vs. moderate AD Cortisol positively correlated with AD severity The combination of cysteine and uridine had 75% sensitivity and specificity for separating mild AD from CN	[44]
CE-MS for non-targeted metabolomics	Test Set: CSF from 19 SCI, 22 stable MCI, 9 MCI progressors, and 23 AD. Validation Set: 4 SCI, 2 stable MCI, 4 MCI progressors, 2 AD.	Based on LDA, correct classification of training set for 94.7% of SCI, 85.7% of MCI-stable; 88.9% of MCI-progressors; and 90.9% of AD For the Test Set, 83% of the samples were correctly assigned to their corresponding group Choline, valine, carnitine, serine, and a tripeptide significantly differed by group in targeted analyses	[45]
UPLC-MS	Plasma from 16 AD, 12 MCI, and 10 CN.	High-influence variables for AD included glycerophosphocholine and D-glucosamininde GCA, GCDCA, and GDCA were increased in MCI and AD vs. CN	[46]
UPLC-MS for global lipidomics 2D GC × GC-TOFMS for global profiling of small polar metabolites	Serum from 46 CN, 37 AD, 52 MCI who progressed to AD, and 91 stable MCI.	AD patients had decreased concentrations of several lipid classes, including phosphatidylcholine, plasmalogens, sphingomyelins, and sterols Dihydroxybutanoic acid best separated MCI patients who did and did not progress to AD over 2 years	[52]
UPLC-ToF-MS	Plasma and CSF from 15 CN, 15 MCI, and 15 AD.	The number of affected pathways in CSF and plasma increased with disease severity In both the CSF and plasma there were significant group differences in pathways related to energy metabolism and mitochondrial function; lipid biosynthesis, trafficking and metabolism; amino acid biosynthesis and metabolism; neurotransmitter biosynthesis and metabolism; and hormone biosynthesis and metabolism	[55]
LC-MS Analyses focused on phospholipids	Plasma from 10 CN, 10 MCI, and 10 AD.	AD and CN had complete group separation Lysophospolipid 18:1 decreased incrementally with increasing disease severity (CN>MCI>AD)	[59]
Liquid chromatography-atmospheric pressure chemical ionization-mass spectroscopy Analyses focused on sterol-related compounds	Test Set: Plasma and CSF from 10 AD and 10 CN. Validation Set: Plasma from 42 CN, 26 MCI, and 41 AD	Plasma and CSF desmosterol was decreased in AD vs. controls Notable sex differences in desmosterol levels and in the sensitivity/specificity of group separations (e.g., MCI vs. AD and MCI vs. CN) Demonstrated importance of methodology as there were no differences in sterol levels when GC-MS was used	[60]
Non-targeted approach using MDMS-SL	Plasma from 26 AD and 26 CN	Long-chain sphingomyelin species were lower in AD patients compared to controls Levels of 2 ceramide species (N16:0 and N21:0) were higher in AD than CN Ratios of ceramide to sphingomyelin species better discriminated between AD cases and CN compared to either lipid species alone	[63]