Recent advances in the application of metabolomics to Alzheimer's Disease (original) (raw)

2013, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

The pathophysiological changes associated with Alzheimer's Disease (AD) begin decades before the emer-33 gence of clinical symptoms. Understanding the early mechanisms associated with AD pathology is, therefore, 34 especially important for identifying disease-modifying therapeutic targets. While the majority of AD clinical 35 trials to date have focused on anti-amyloid-beta (Aβ) treatments, other therapeutic approaches may be nec-36 essary. The ability to monitor changes in cellular networks that include both Aβ and non-Aβ pathways is es-37 sential to advance our understanding of the etiopathogenesis of AD and subsequent development of cognitive 38 symptoms and dementia. Metabolomics is a powerful tool that detects perturbations in the metabolome, a 39 pool of metabolites that reflects changes downstream of genomic, transcriptomic and proteomic fluctuations, 40 and represents an accurate biochemical profile of the organism in health and disease. The application of 41 metabolomics could help to identify biomarkers for early AD diagnosis, to discover novel therapeutic targets, 42 and to monitor therapeutic response and disease progression. Moreover, given the considerable parallel be-43 tween mouse and human metabolism, the use of metabolomics provides ready translation of animal research 44 into human studies for accelerated drug design. In this review, we will summarize current progress in the ap-45 plication of metabolomics in both animal models and in humans to further understanding of the mechanisms 46 involved in AD pathogenesis. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial 47 Dysfunction and Neurodegenerative Diseases. 48 F 74 mechanisms that contribute to the development of AD pathology, as 75 well as to the emergence of cognitive symptoms and dementia. 76 While Aβ is essential for a diagnosis of AD (including preclinical 77 AD for research purposes based on the National Institute of Aging-78 the Alzheimer's Association (NIAAA) criteria), it is not sufficient to ul-79 timately cause cognitive impairment and dementia. Approximately 80 30% of individuals aged 70 and older do not develop cognitive impair-81 ment or dementia despite having significant amyloid load detected 82 with magnetic resonance imaging (MRI) [11,12]. Therefore, in order 83 to better understand the etiopathogenesis of AD, it is necessary to 84 focus on both Aβ and non-Aβ pathways to advance our understanding 85 of early disease mechanisms and to develop efficient therapeutic ap-86 proaches. Previous studies have suggested that non-Aβ mechanisms 87 including calcium dysregulation, mitochondrial dysfunction, altered 88 cell signaling, oxidative stress, inflammation, and lipid homeostasis 89 are perturbed in AD [13,14]. However, the temporal relationship between