Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

A. Dehghan; R.C. Pinto; I. Karaman; J. Huang; B.R. Durainayagam; M. Ghanbari; A. Nazeer; Q. Zhong; S. Liggi; L. Whiley; R. Mustafa; M. Kivipelto; A. Solomon; T. Ngandu; T. Kanekiyo; T. Aikawa; C.I. Radulescu; S.J. Barnes; G. Graça; E. Chekmeneva; S. Camuzeaux; M.R. Lewis; M.R. Kaluarachchi; M.A. Ikram; E. Holmes; I. Tzoulaki; P.M. Matthews; J.L. Griffin; P. Elliott

doi:10.1073/pnas.2206083119

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Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

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Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

A. Dehghan, R.C. Pinto, I. Karaman, J. Huang, B.R. Durainayagam, M. Ghanbari, A. Nazeer, Q. Zhong, S. Liggi, L. Whiley, …

Proceedings of the National Academy of Sciences, Vol.119(43), e2206083119

2022

DOI: https://doi.org/10.1073/pnas.2206083119

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Abstract

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.

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Title: Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
Authors/Creators: A. Dehghan (Author/Creator) - Imperial College London
R.C. Pinto (Author/Creator) - Imperial College London
I. Karaman (Author/Creator) - Imperial College London
J. Huang (Author/Creator) - Imperial College London
B.R. Durainayagam (Author/Creator) - Imperial College London
M. Ghanbari (Author/Creator) - Erasmus University Rotterdam
A. Nazeer (Author/Creator) - Imperial College London
Q. Zhong (Author/Creator) - Hammersmith Hospital
S. Liggi (Author/Creator) - Imperial College London
L. Whiley (Author/Creator) - Murdoch University
R. Mustafa (Author/Creator) - Imperial College London
M. Kivipelto (Author/Creator) - University of Eastern Finland
A. Solomon (Author/Creator) - Imperial College London
T. Ngandu (Author/Creator) - Karolinska Institutet
T. Kanekiyo (Author/Creator) - Mayo Clinic in Florida
T. Aikawa (Author/Creator) - Mayo Clinic in Florida
C.I. Radulescu (Author/Creator) - Hammersmith Hospital
S.J. Barnes (Author/Creator) - Hammersmith Hospital
G. Graça (Author/Creator) - Imperial College London
E. Chekmeneva (Author/Creator) - Imperial College London
S. Camuzeaux (Author/Creator) - Imperial College London
M.R. Lewis (Author/Creator) - Imperial College London
M.R. Kaluarachchi (Author/Creator) - Imperial College London
M.A. Ikram (Author/Creator) - Erasmus University Rotterdam
E. Holmes (Author/Creator) - Hammersmith Hospital
I. Tzoulaki (Author/Creator) - Imperial College London
P.M. Matthews (Author/Creator) - Hammersmith Hospital
J.L. Griffin (Author/Creator) - Hammersmith Hospital
P. Elliott (Author/Creator) - Imperial College London
Publication Details: Proceedings of the National Academy of Sciences, Vol.119(43), e2206083119
Publisher: National Academy of Sciences
Identifiers: 991005544922307891
Copyright: © 2022 The Author(s).
Murdoch Affiliation: Australian National Phenome Centre; Centre for Computational and Systems Medicine
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 2 Chemistry; 2.211 Mass Spectrometry; 2.211.990 Metabolomics
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior