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Differences in plasma metabolites related to Alzheimer's disease, APOE ?4 status, and ethnicity.

ABSTRACT: Introduction:We investigated metabolites in plasma to capture systemic biochemical changes associated with Alzheimer's disease (AD). Methods:Metabolites in plasma were measured in 59 AD cases and 60 healthy participants of African American (AA), Caribbean Hispanic (CH), and non-Hispanic white (NHW) ancestry using untargeted liquid-chromatography-based ultra-high-resolution mass spectrometry. Metabolite differences between AD and healthy, ethnic groups and apolipoprotein E gene (APOE) ?4 status were analyzed. Untargeted network analysis identified pathways enriched in AD-associated metabolites. Results:A total of 5929 annotated metabolites were measured. Partial least squares discriminant analysis (PLS-DA) inferred that AD clustered separately from healthy controls (area under the curve [AUC] = 0.9816); discriminating pathways included glycerophospholipid, sphingolipid, and non-essential amino acid (alanine, aspartate, glutamate) metabolism. Metabolic features in AA clustered differently from CH and NHW (AUC = 0.9275), and differed between APOE ?4 carriers and non-carriers (AUC = 0.9972). Discussion:Metabolites, specifically lipids, were associated with AD, APOE ?4, and ethnic group. Metabolite profiling can identify perturbed AD pathways, but genetic and ancestral background need to be considered.

SUBMITTER: Vardarajan B

PROVIDER: S-EPMC7201178 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Differences in plasma metabolites related to Alzheimer's disease, <i>APOE</i> ε4 status, and ethnicity.

Vardarajan Badri B Kalia Vrinda V Manly Jennifer J Brickman Adam A Reyes-Dumeyer Dolly D Lantigua Rafael R Ionita-Laza Iuliana I Jones Dean P DP Miller Gary W GW Mayeux Richard R

Alzheimer's & dementia (New York, N. Y.) 20200506 1

<h4>Introduction</h4>We investigated metabolites in plasma to capture systemic biochemical changes associated with Alzheimer's disease (AD).<h4>Methods</h4>Metabolites in plasma were measured in 59 AD cases and 60 healthy participants of African American (AA), Caribbean Hispanic (CH), and non-Hispanic white (NHW) ancestry using untargeted liquid-chromatography-based ultra-high-resolution mass spectrometry. Metabolite differences between AD and healthy, ethnic groups and apolipoprotein E gene (<i ...[more]

PMID: 32377558

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Project description:APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and accounts for 50-65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE ε4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE ε4 stratification. Two specific modules were identified in AD APOE ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE ε4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE ε4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE ε4 non-carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE ε4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE ε4 treatment but not under APOE ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers' module was correlated under APOE ε3 treatment but not under APOE ε4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson's disease. These data demonstrate that AD in APOE ε4 carriers involves more genetic factors and particular biological processes, whereas AD in APOE ε4 non-carriers shares more common pathways with other types of diseases. The study reveals differential genetic bases and pathogenic and pathological processes between carriers and non-carriers, providing new insight into the mechanisms of the differences between APOE ε4 carriers and non-carriers in AD.

Dataset Information

Differences in plasma metabolites related to Alzheimer's disease, APOE ?4 status, and ethnicity.

Publications

Differences in plasma metabolites related to Alzheimer's disease, <i>APOE</i> ε4 status, and ethnicity.

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