{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:28:42Z","timestamp":1777494522525,"version":"3.51.4"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":42,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2022-01643"],"award-info":[{"award-number":["2022-01643"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011751","name":"Swedish Foundation for Strategic Research","doi-asserted-by":"publisher","award":["KF10-0039"],"award-info":[{"award-number":["KF10-0039"]}],"id":[{"id":"10.13039\/501100011751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["FO2022-0217"],"award-info":[{"award-number":["FO2022-0217"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish Government under the LUA\/ALF","award":["ALFGBG-965444"],"award-info":[{"award-number":["ALFGBG-965444"]}]},{"DOI":"10.13039\/100001388","name":"Wenner-Gren Foundation","doi-asserted-by":"publisher","award":["SSv2019-0008"],"award-info":[{"award-number":["SSv2019-0008"]}],"id":[{"id":"10.13039\/100001388","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Parkinson\u2019s Disease UK","award":["PRO-20-00"],"award-info":[{"award-number":["PRO-20-00"]}]},{"name":"Peto Foundation"},{"name":"European Union H2020 \u2018Adage\u2019"},{"name":"Biological Mass Spectrometry Research Centre"},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019256","name":"NIHR Great Ormond Street Hospital Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019256","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The \u03b54 allele of the APOE gene, encoding the E4 isoform of apolipoprotein E, is the leading genetic risk factor for late-onset Alzheimer\u2019s disease. While many potential mechanisms have been proposed to explain this risk, no dominant or unifying process has yet emerged. Here, we explore the primary function of apolipoprotein E in lipid transport and metabolism, by examining its lipid association properties, to establish whether they show isoform dependence and thereby could mediate Alzheimer\u2019s risk. We focus on ethanolamine plasmalogen, a phospholipid subclass known to be depleted in Alzheimer\u2019s disease brain. We purified apolipoprotein E from human cerebrospinal fluid by immunoprecipitation using an anti-pan-apolipoprotein E monoclonal antibody bound to magnetic beads, then conducted lipidomic and proteomic analyses of the precipitates by mass spectrometry. The cerebrospinal fluid samples were obtained from cognitively intact, relatively young individuals with no evidence of amyloid pathology and with known apolipoprotein E isoform status (E3E3, n = 5; E3E4, n = 4; E4E4, n = 5). The molar ratio of ethanolamine plasmalogen to apolipoprotein E was 29.5% lower for E4E4 than for E3E3 (P = 0.007) with a biological gradient: E3E3 &amp;gt; E3E4 &amp;gt; E4E4 (P = 0.03). No similar trends and differences were found for phosphatidyl ethanolamine, a chemically related lipid (P = 0.5). Compared to E3E3, the molar ratio of ethanolamine plasmalogen to phosphatidyl ethanolamine was significantly reduced for E3E4 (P = 0.0016) and E4E4 (P = 0.0001). The latter deficiency was similar in magnitude to that found in Alzheimer\u2019s disease brain relative to control. The finding that ethanolamine plasmalogen is depleted in apolipoprotein E4 relative to E3 strengthens the view that brain deficiency of this same lipid contributes to Alzheimer\u2019s disease causation, rather than being an effect of the neurodegeneration. Simultaneously, these results supply a potential mechanism for the risk of E4 versus E3, the former being less able to counteract the tissue defect. The apolipoprotein E4 lipid depletion cannot itself be a consequence of Alzheimer\u2019s disease, since cerebrospinal fluid samples were taken from individuals with no evidence of the condition. The biological gradient in ethanolamine plasmalogen deficiency mirrors the relationship of Alzheimer\u2019s disease risk (odds ratio) to E4 allelic dose. Ethanolamine plasmalogen deficiency could be linked to, or indeed drive, several metabolic pathways implicated in Alzheimer\u2019s pathogenesis, including amyloid-beta deposition and cholesterol dysregulation. Future studies should extend approaches to therapeutic intervention in Alzheimer\u2019s disease which attempt to reverse this lipid abnormality.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag040","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T12:41:00Z","timestamp":1770813660000},"source":"Crossref","is-referenced-by-count":1,"title":["Plasmalogen deficiency and the Alzheimer\u2019s disease risk of apolipoprotein E4"],"prefix":"10.1093","volume":"8","author":[{"given":"Jenny","family":"H\u00e4llqvist","sequence":"first","affiliation":[{"name":"Translational Mass Spectrometry Research Group, UCL Great Ormond Street Institute of Child Health , London WC1N 1EH ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan-Willem","family":"Taanman","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology , London NW3 2PF ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"G\u00f6teson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg , Gothenburg 431 41 ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-8760","authenticated-orcid":false,"given":"Wendy E","family":"Heywood","sequence":"additional","affiliation":[{"name":"Translational Mass Spectrometry Research Group, UCL Great Ormond Street Institute of Child Health , London WC1N 1EH ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2059-024X","authenticated-orcid":false,"given":"Jonathan M","family":"Schott","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Hardy","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"UK Dementia Research Institute, University College London , London W1T 7NF ,","place":["UK"]},{"name":"Reta Lila Weston Institute, UCL Queen Square Institute of Neurology , London WC1N 1PJ ,","place":["UK"]},{"name":"Institute for Advanced Study, The Hong Kong University of Science and Technology , Hong Kong SAR ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikael","family":"Land\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg , Gothenburg 431 41 ,","place":["Sweden"]},{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm 171 77 ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg , Gothenburg 431 41 ,","place":["Sweden"]},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"UK Dementia Research Institute, University College London , London W1T 7NF ,","place":["UK"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal 413 45 ,","place":["Sweden"]},{"name":"Hong Kong Center for Neurodegenerative Diseases , Clear Water Bay, Hong Kong SAR ,","place":["China"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Mills","sequence":"additional","affiliation":[{"name":"Translational Mass Spectrometry Research Group, UCL Great Ormond Street Institute of Child Health , London WC1N 1EH ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3159-3166","authenticated-orcid":false,"given":"Lionel","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology , London NW3 2PF ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"2026022701112248000_fcag040-B1","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.neuron.2022.03.004","article-title":"ApoE cascade hypothesis in the pathogenesis of Alzheimer\u2019s disease and related 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Alzheimer disease","volume":"71","author":"Lautner","year":"2014","journal-title":"JAMA Psychiatry"},{"key":"2026022701112248000_fcag040-B24","author":"Taanman","year":"2023"},{"key":"2026022701112248000_fcag040-B25","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3390\/metabo12030230","article-title":"Lipid profiles of human serum fractions enhanced with CD9 antibody-immobilized magnetic beads","volume":"12","author":"Tokuoka","year":"2022","journal-title":"Metabolites"},{"key":"2026022701112248000_fcag040-B26","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/s42255-022-00628-3","article-title":"Introducing the lipidomics minimal reporting checklist","volume":"4","author":"McDonald","year":"2022","journal-title":"Nat Metab"},{"key":"2026022701112248000_fcag040-B27","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1016\/j.jasms.2004.07.009","article-title":"Electrospray ionization tandem mass spectrometry of glycerophosphoethanolamine plasmalogen 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