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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.

Original publication

DOI

10.1073/pnas.2206083119

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

10/2022

Volume

119

Addresses

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London SW7 2AZ, United Kingdom.

Keywords

Animals, Mice, Knockout, Mice, Alzheimer Disease, Ceramides, Lactosylceramides, Sphingomyelins, ATP-Binding Cassette Transporters, Chromatography, Liquid, Tandem Mass Spectrometry, Genome-Wide Association Study, Metabolome