Gas chromatography coupled to mass spectrometry is the most frequent tool for metabolomic profiling of low molecular weight metabolites. Its suitability in health survey is beyond doubt, given that primary metabolites involved in central pathways of metabolism are usually altered in diseases. The objective of this work is to investigate metabolic differences in serum between Alzheimer's disease patients and healthy controls in order to elucidate pathological mechanisms underlying to disease. Alterations in levels of 23 metabolites were detected, including increased lactic acid, α-ketoglutarate, isocitric acid, glucose, oleic acid, adenosine and cholesterol, as well as decreased urea, valine, aspartic acid, pyroglutamate, glutamine, phenylalanine, asparagine, ornithine, pipecolic acid, histidine, tyrosine, palmitic and uric acid, tryptophan, stearic acid and cystine. Metabolic pathway analysis revealed the involvement of multiple affected pathways, such as energy deficiencies, oxidative stress, hyperammonemia, and others. Moreover, it is noteworthy that some of these compounds have not been previously described in AD research, such as α-ketoglutarate, isocitrate pipecolic acid, pyroglutamate and adenosine, confirming the potential of this metabolomic approach in the search of novel potential markers for early detection of Alzheimer's disease.

Alzheimer's disease is closely related to abnormal metabolism of phospholipids from neural membranes, so that the study of their dyshomeostasis could be of great interest for the discovery of potential biomarkers for diagnosis and disease monitoring. In this work, it has been developed a metabolomic multi-platform for the characterization of phospholipid alterations occurring in serum from Alzheimer's disease patients. For this purpose, we performed a metabolomic screening by direct infusion mass spectrometry and profiling analysis by reversed phase ultra-high performance liquid chromatography with complementary detection by molecular and atomic mass spectrometry, which allowed combining the high-throughput capability of shotgun metabolomics and the targeted character of profiling approaches. Thus significant changes were detected in the levels of several molecular species of phosphatidylcholines, phosphatidylethanolamines, plasmenylcholines, plasmenylethanolamines and different classes of lysophospholipids, which provided a global vision of the possible factors triggering membrane breakdown. In this sense, alterations of phospholipids metabolism appears to have a multifactorial origin involving overactivation of phospholipases, increased anabolism of lysophospholipids, peroxisomal dysfunction, imbalances in the levels of saturated/unsaturated fatty acids contained in the structure of phospholipids and oxidative stress. This work represents the first comprehensive characterization of serum phospholipids alterations in relation to Alzheimer's disease, by combining shotgun metabolomics and phospholipids profiling through different analytical approaches.This article is part of a Special Issue entitled: Environmental and structural proteomics.