Differences in Plasma Metabolites Related to Alzheimer's Disease, APOE-e4 Status and Ethnicity

Importance. Metabolomics can provide insight into molecular mechanisms within biochemical pathways leading to disease or in vivo changes that result from the disease. Objective. The goal of this investigation was to identify metabolites in plasma that capture systemic biochemical changes associated with Alzheimer disease (AD). Design. Plasma from individuals in a multi-ethnic, community-based cohort study underwent untargeted liquid chromatography (LC)-based ultra-high resolution mass spectrometry (LC-UHRMS) to test for hydrophilic and lipophilic chemicals derived from endogenous and exogenous sources. Each metabolite was tested for association with AD adjusting for age, sex and racial/ethnic group using the mixOmics package in R. Additional models were tested adjusting for the presence of APOE e4 alleles. Metabolites that differed between ethnic groups were also analyzed. An untargeted pathway analysis, using the network analysis software Mummichog, was conducted to identify pathways enriched in metabolites associated with AD. Setting. Multi-ethnic, community-based, case-control study. Participants. Participants from the Washington Heights, Inwood, Columbia Aging Project (WHICAP) of African American, Caribbean Hispanic and European ancestry provided blood samples from which plasma was extracted. Main Outcome. Metabolomics profiles associated with AD. Results. Over 9,700 features were measured, of which 5,929 were annotated by xMSannotator. Partial least squares-discriminant analysis showed that AD clustered separately from healthy controls (AUC=0.9816); after adjusting for age, sex and ethnic group, discriminating pathways included glycerophospholipid, sphingolipid and non-essential amino acid (alanine, aspartate, glutamate) metabolism. Metabolic features obtained in African Americans clustered differently than those in the Caribbean Hispanics and non-Hispanic whites (AUC=0.9275), and there was a near complete separation between APOE e4 carriers and non-carriers irrespective of disease status (AUC=0.9972). Conclusions and Relevance. Metabolites, specifically lipids, were found to be associated with AD, APOE e4 and ethnic group. Metabolite profiling in plasma could facilitate the identification of perturbed metabolic pathways in AD, but genetic and ancestral background need to be considered.