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 × 10-5 to 1.3 × 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 × 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.
|Number of pages||12|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 25 Oct 2022|
Bibliographical noteThe authors thank Prof. Takashi Saito, Nagoya City University Graduate School of Medical Sciences, Japan and Prof. Takomi Saido, RIKEN Centre for Brain Science, Japan for access to the AppNL-G-F mouse model. The authors also want to thank Dr. Jenny Hällqvist for helping to illustrate Fig. 7. This work is supported by the UK Dementia Research Institute at Imperial College, which receives its funding from UK Dementia Research Institute Ltd., funded by the UK Medical Research Council (MRC), Alzheimer’s Society, and Alzheimer’s Research UK. A.D. is funded by a Wellcome Trust seed award (206046/Z/17/Z). R.M. is funded by the President’s PhD Scholarship from Imperial College London. P.M.M. acknowledges generous personal and research support from the Edmond J. Safra Foundation and Lily Safra and a National Institute for Health Research (NIHR) Senior Investigator Award (to 2020). J.L.G. is funded by the MRC (MC_UP_A090_1006, MC_PC_13030, MR/P011705/1, MR/P01836X/1
, and MR/S010483/1) and Wellcome Trust (MetaboFlow). M.K. is funded by the NIHR Imperial Biomedical Research Centre (BRC), Wallenberg Clinical Scholars, Academy of Finland, and Swedish Research Council. A.S. is funded by the Academy of Finland (287490, 294061, and 319318), European Research Council (804371), Alzheimerfonden, and Region Stockholm ALF (Sweden). This work was supported by the MRC and NIHR (grant No. MC_PC_12025). P.E. is the director of the MRC Centre for Environment and Health (MR/L01341X/1). He acknowledges support from the NIHR Health Protection Research Units in Chemical and Radiation Threats and Hazards and Health Impact of Environmental Hazards. P.E. is a codirector of the Health Data Research UK London site, which is supported, among others, by MRC, NIHR, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Wellcome Trust, and British Heart Foundation (BHF). P.E. acknowledges support from the BHF Centre for Research Excellence at Imperial College. Infrastructure support for this research was provided by the NIHR Imperial BRC Science.
Data Availability StatementAll summary statistics for association data are included in the manuscript and/or supporting information. All AIRWAVE metabolomic data sets are available for download here https://doi.org/10.14469/hpc/6945 (71). All other AIRWAVE data may be accessed upon application to the Dementias Platform UK Data portal (https://portal.dementiasplatform.uk/Apply/ApplicationProcess) (72). The FINGER data presented in this article are not readily available because data can be made available only for those fulfilling the requirements for viewing confidential data as required by Finnish law and the Finnish Institute for Health and Welfare. Moreover, the purpose of the research must be in alignment with the informed consent provided for this study and/or the FINGER study, with Finnish law and regulations at the Finnish Institute for Health and Welfare. Requests are to be submitted to the Finnish Institute for Health and Welfare: email@example.com. Data for the Rotterdam Study can be obtained upon request. Requests should be directed toward the management team of the Rotterdam Study (firstname.lastname@example.org), which has a protocol for approving data requests. Because of restrictions based on privacy regulations and the informed consent of the participants, data cannot be made freely available in a public repository. Data for ABCA7 KO mice is available here https://www.ebi.ac.uk/metabolights/MTBLS6093 (73).
- Alzheimer’s disease
- genome-wide association study