Abstract
The expending of elderly population worldwide has resulted in a dramatic rise in the incidence of chronic diseases such as Alzheimer's disease (AD). Inadequate understanding of the mechanisms underlying AD has hampered the development of efficient tools for definitive diagnosis and curative interventions. Previous studies have attempted to discover reliable biomarkers of AD, but these biomarkers can only be measured through invasive (neuropathological markers in cerebrospinal fluid) or expensive (positron emission tomography scanning or magnetic resonance imaging) techniques. Metabolomics is a high-throughput technology that can detect and catalog large numbers of small metabolites and may be a useful tool for characterization of AD and identification of biomarkers. In this study, we used ultra-performance liquid chromatography-mass spectrometry based untargeted metabolomics to measure the concentrations of plasma metabolites in a cohort of subjects with AD (n=44) and cognitively normal controls (Ctrl, n=94). The AD group showed marked reductions in levels of polyunsaturated fatty acids, acyl-carnitines, degradation products of tryptophan, and elevated levels of bile acids compared to the Ctrl group. We then validated the results using an independent cohort that included subjects with AD (n=30), mild cognitive impairment (MCI, n=13), healthy controls (n=43), and non-AD neurological disease controls (NDC, n=31). We identified five metabolites comprising cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid, and tryptophan that were able to distinguish patients with AD from both Ctrl and NDC with satisfactory sensitivity and specificity. The concentrations of these metabolites were significantly correlated with disease severity. Our results also suggested that altered bile acid profiles in AD and MCI might indicate early risk for the development of AD. These findings may allow for development of new approaches for diagnosis of AD and may provide novel insights into AD pathogenesis.