Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 43, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2206083119
Keywords
genome-wide association study; Alzheimer's disease; ABCA7; metabolomics; ceramide
Categories
Funding
- UK Dementia Research Institute at Imperial College from UK Dementia Research Institute Ltd - UK Medical Research Council (MRC)
- Alzheimer's Society
- Wellcome Trust [206046/Z/17/Z]
- Imperial College London
- Edmond J. Safra Foundation
- MRC [MC_UP_A090_1006, MC_PC_13030, MR/P011705/1, MR/P01836X/1, MR/S010483/1]
- President's PhD Scholarship from Imperial College London
- Edmond J. Safra Foundation and Lily Safra
- National Institute for Health Research (NIHR)
- NIHR Imperial Biomedical Research Centre (BRC)
- Wallenberg Clinical Scholars
- Academy of Finland
- Swedish Research Council
- Academy of Finland [287490, 294061, 319318]
- European Research Council [804371]
- Alzheimerfonden
- Region Stockholm ALF (Sweden)
- MRC
- NIHR [MC_PC_12025]
- MRC Centre for Environment and Health [MR/L01341X/1]
- BHF Centre for Research Excellence at Imperial College
- Wellcome Trust [206046/Z/17/Z] Funding Source: Wellcome Trust
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Genome-wide association studies have identified genetic loci associated with the risk of Alzheimer's disease (AD). In this study, we used metabolomics to investigate the molecular mechanisms underlying these associations. We found an association between lactosylceramides and AD-related single-nucleotide polymorphisms in the ABCA7 gene. We also observed altered concentrations of certain lipids in brain tissue from knockout mice, suggesting that these lipid abnormalities may contribute to the risk of AD.
Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 x 10(-5) to 1.3 x 10(-44)). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 x 10(-5)), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.
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