Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer’s Disease

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.

Biomarkers and Their Implications in Alzheimer’s Disease: A Literature Review

“…Dysregulation of several metabolic pathways with changes in plasma metabolites has been associated with and may contribute to AD pathology and impairment. 5 Cholesterol metabolism, fatty acid (FA) metabolism, bile acid synthesis, and amino acid metabolism may be the most associated with AD. Therefore, changes in plasma FAs, bile acids, and amino acids are some of the most apparent alterations reported in previous studies.…”

“…Therefore, changes in plasma FAs, bile acids, and amino acids are some of the most apparent alterations reported in previous studies. 5,[144][145][146] The reduction in the level of polyunsaturated fatty acids (PUFA), particularly docosahexaenoic acid (DHA), has been associated with cognitive impairment due to AD and may be due to impaired FA metabolism in the liver. 5,147, 148 One study showed that cognitive performance improved with dietary supplementation of DHA in AD patients, which could have been due to neuroprotective properties of PUFAs.…”

“…148,149 To further implicated liver dysfunction, the level of the bile acids cholic acid, chenodeoxycholic acid, and allocholic acid all increased with disease severity in AD. 5 The role of bile acids as biomarkers in AD is further propounded by evidence of association between the traditional AD biomarkers, Aβ and tau, and bile acid profiles. 5,150 Regarding alterations in FA metabolism, studies have shown declining acyl-carnitines across subjects from healthy individuals to those with MCI and AD, with significantly reduced levels of medium-and long-chain acyl-carnitines in those with AD.…”

“…5 The role of bile acids as biomarkers in AD is further propounded by evidence of association between the traditional AD biomarkers, Aβ and tau, and bile acid profiles. 5,150 Regarding alterations in FA metabolism, studies have shown declining acyl-carnitines across subjects from healthy individuals to those with MCI and AD, with significantly reduced levels of medium-and long-chain acyl-carnitines in those with AD. 5,151 Impaired energy metabolism is further indicated by one study that analyzed RNA transcripts to find decreased beta-oxidation, mitochondrial transport, and carnitine shuttle activity in patients with AD.…”

“…3 More than 95% of AD cases are sporadic in nature, with only 1-5% resulting from a genetic disposition. 5 The accumulation of amyloid plaques or amyloid-B (Aβ) peptides in the extracellular neural tissue and neurofibrillary tangles (NFT) composed of hyper-phosphorylated tau proteins within the intracellular tissue of the brain are the main pathological signs of AD. 2,6,7 However, several other factors have been described as significant contributors to the pathogenesis of AD.…”