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However, tau aggregate polymorphism across the apolipoprotein E isoforms (\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b52, \u03b53, \u03b54), the strongest predictors of late\u2010onset AD development, is unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      This study assessed the conformational and bioactivity properties of tau oligomers from 14 patients with varying\n                      <jats:italic>APOE<\/jats:italic>\n                      genotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Tau oligomers differ in proteolytic stability and cleavage site profiles across the\n                      <jats:italic>APOE<\/jats:italic>\n                      isoforms, indicating conformationally distinct polymorphs.\n                      <jats:italic>APOE<\/jats:italic>\n                      isoform\u2010associated tau oligomers affect synaptic plasticity differently, with \u03b54\u2010associated oligomers having the highest potency and strongest impact on synaptic functioning. Bioactivity assays reveal that \u03b54\u2010associated oligomers demonstrate particularly high seeding activity. Interestingly, tau oligomer synaptotoxicity and seeding activity are independent characteristics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>APOE<\/jats:italic>\n                      isoforms are associated with distinct tau oligomer polymorphs with varying bioactivity, underscoring the importance of considering\n                      <jats:italic>APOE<\/jats:italic>\n                      status when generating AD therapies. Polymorph\u2010specific targeting of pathological tau species could provide a novel method of combating AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Conformational and bioactivity distinctions of tau oligomers have not yet been investigated across the\n                            <jats:italic>APOE<\/jats:italic>\n                            isoforms (\u03b52, \u03b53, \u03b54).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Tau oligomers differ in conformational properties across the\n                            <jats:italic>APOE<\/jats:italic>\n                            isoforms.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>APOE<\/jats:italic>\n                            \u03b54\u2010relevant tau oligomers strongly impair synaptic plasticity and demonstrate high tau seeding activity.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>APOE<\/jats:italic>\n                            \u03b54\u2010relevant tau oligomers exist as a particularly toxic species, making them an ideal target for tau\u2010based AD therapies.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70965","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T09:32:48Z","timestamp":1765618368000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["APOE isoform\u2010associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0482-1394","authenticated-orcid":false,"given":"Naomi","family":"Moreno","sequence":"first","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases University of Texas Medical Branch  Galveston Texas USA"},{"name":"Department of Neurology, Neuroscience, and Cell Biology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Shchankin","sequence":"additional","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases University of Texas Medical Branch  Galveston Texas USA"},{"name":"Department of Neurology, Neuroscience, and Cell Biology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leiana","family":"Fung","sequence":"additional","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases University of Texas Medical Branch  Galveston Texas USA"},{"name":"Department of Neurology, Neuroscience, and Cell Biology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicha","family":"Puangmalai","sequence":"additional","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases University of Texas Medical Branch  Galveston Texas USA"},{"name":"Department of Neurology, Neuroscience, and Cell Biology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nemil","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases University of Texas Medical Branch  Galveston Texas USA"},{"name":"Department of Neurology, Neuroscience, and Cell Biology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Anzarul","family":"Haque","sequence":"additional","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases University of Texas Medical Branch  Galveston Texas USA"},{"name":"Department of Neurology, Neuroscience, and Cell Biology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Sealy Center for Molecular Medicine University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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