{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:08:24Z","timestamp":1791925704714,"version":"4.3.4"},"reference-count":61,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007457","name":"JPB Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007457","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG047644"],"award-info":[{"award-number":["AG047644"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS090932"],"award-info":[{"award-number":["NS090932"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late\u2010onset Alzheimer's disease, with the \u03b54 allele increasing risk in a dose\u2010dependent fashion. In addition to ApoE4 playing a crucial role in amyloid\u2010\u03b2 deposition, recent evidence suggests that it also plays an important role in tau pathology and tau\u2010mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau\u2010mediated neurodegeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Herein, we used antisense oligonucleotides (ASOs) against human <jats:italic>APOE<\/jats:italic> to reduce ApoE4 levels in the P301S\/ApoE4 mouse model of tauopathy. We treated P301S\/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5\u2009months of age and performed brain pathological assessments at 9\u2009months of age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO\u2010treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for <jats:italic>APOE4<\/jats:italic> carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952\u2013966<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26043","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T19:14:39Z","timestamp":1612811679000},"page":"952-966","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model"],"prefix":"10.1002","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0591-7948","authenticated-orcid":false,"given":"Alexandra","family":"Litvinchuk","sequence":"first","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8375-7938","authenticated-orcid":false,"given":"Tien\u2010Phat V.","family":"Huynh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"},{"name":"Medical Scientist Training Program (MSTP) Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5441-0529","authenticated-orcid":false,"given":"Yang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5478-5611","authenticated-orcid":false,"given":"Rosemary J.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital  Charlestown MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary B.","family":"Finn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Manis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline M.","family":"Francis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainsley C.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8402-2634","authenticated-orcid":false,"given":"Patrick M.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center's Geriatric Research Education and Clinical Center  Durham NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-926X","authenticated-orcid":false,"given":"Jason D.","family":"Ulrich","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center Washington University School of Medicine  St. Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-9401","authenticated-orcid":false,"given":"Bradley T.","family":"Hyman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital  Charlestown MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Cole","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  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