Date Published: January 25, 2018
Publisher: Public Library of Science
Author(s): Vijay R. Varma, Anup M. Oommen, Sudhir Varma, Ramon Casanova, Yang An, Ryan M. Andrews, Richard O’Brien, Olga Pletnikova, Juan C. Troncoso, Jon Toledo, Rebecca Baillie, Matthias Arnold, Gabi Kastenmueller, Kwangsik Nho, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, Cristina Legido-Quigley, Madhav Thambisetty, Carol Brayne
Abstract: BackgroundThe metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.Methods and findingsQuantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer’s Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703–11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516–7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373–9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047–4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples.ConclusionsWe present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
Partial Text: The relationships between systemic abnormalities in metabolism and the pathogenesis of Alzheimer disease (AD) are poorly understood. It is unclear how global perturbations in metabolism are related to severity of AD pathology and the eventual expression of AD symptoms in at-risk individuals. Understanding the metabolic basis of AD and its impact on disease progression during the early, preclinical, and prodromal stages is likely to provide insights into novel disease-modifying treatments for this irreversible, progressive neurodegenerative disorder.
To the best of our knowledge, this is the first study to apply quantitative and targeted metabolomic analyses of both brain and blood tissue to identify metabolites associated with the severity of AD pathology as well as measures of AD progression. Our results indicate that distinct metabolites belonging to the sphingolipid and glycerophospholipid classes are related to the severity of AD pathology in the brain and that their concentrations in blood are associated with preclinical disease progression. Furthermore, we were able to identify these specific metabolites through a data-driven process that first used machine-learning methods to generate an AD-specific brain metabolite signature, and then clustered these metabolites based on the EASE-AD summary score representing cumulative associations of each metabolite, with outcome measures related to AD pathology and progression.