{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T06:31:19Z","timestamp":1793082679592,"version":"4.5.0"},"reference-count":73,"publisher":"National Academy of Sciences","issue":"43","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,25]]},"abstract":"<jats:p>\n                    Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer\u2019s 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\u2013mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in\n                    <jats:italic>ABCA7<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 5.0 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    to 1.3 \u00d7 10\n                    <jats:sup>\u221244<\/jats:sup>\n                    ). 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\n                    <jats:italic>Abca7<\/jats:italic>\n                    knockout mice, compared with wild type (WT) (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.049\u20131.4 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ), 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\n                    <jats:italic>ABCA7<\/jats:italic>\n                    is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2206083119","type":"journal-article","created":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T14:41:44Z","timestamp":1666363304000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":41,"title":["Metabolome-wide association study on\n                    <i>ABCA7<\/i>\n                    indicates a role of ceramide metabolism in Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6403-016X","authenticated-orcid":false,"given":"Abbas","family":"Dehghan","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London SW7 2AZ, United Kingdom"},{"name":"Medical Research Council Centre for Environment and Health, School of 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