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Background  Alzheimer's disease (AD) is one of the most common causes of dementia in old people. Neuronal deficits such as loss of memory, language and problem-solving are severely compromised in affected patients. The molecular features of AD are Aβ deposits in plaques or in oligomeric structures and neurofibrillary tau tangles in brain. However, the challenge is that Aβ is only one piece of the puzzle, and recent findings continue to support the hypothesis that their presence is not sufficient to predict decline along the AD outcome. In this regard, metabolomic-based techniques are acquiring a growing interest for either the early diagnosis of diseases or the therapy monitoring. Mass spectrometry is one the most common analytical platforms used for detection, quantification, and characterization of metabolic biomarkers. In the past years, both targeted and untargeted strategies have been applied to identify possible interesting compounds.    Aim of review  The overall goal of this review is to guide the reader through the most recent studies in which LC–MS-based metabolomics has been proposed as a powerful tool for the identification of new diagnostic biomarkers in AD. To this aim, herein studies spanning the period 2009–2020 have been reported. Advantages and disadvantages of targeted vs untargeted metabolomic approaches have been outlined and critically discussed.

Challenges in LC–MS-based metabolomics for Alzheimer’s disease early detection: targeted approaches versus untargeted approaches