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The goal of this study is to address how APOE isoforms impact TDP\u201043 pathology and related neurodegeneration in the absence of typical AD pathologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We overexpressed human TDP\u201043 via viral transduction in humanized <jats:italic>APOE2<\/jats:italic>, <jats:italic>APOE3<\/jats:italic>, <jats:italic>APOE4<\/jats:italic> mice, and murine <jats:italic>Apoe<\/jats:italic>\u2010knockout (<jats:italic>Apoe<\/jats:italic>\u2010KO) mice. Behavior tests were performed across ages. Animals were harvested at 11\u00a0months of age and TDP\u201043 overexpression\u2010related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of <jats:italic>APOE<\/jats:italic> with TDP\u201043 pathology in 160 postmortem brains from autopsy\u2010confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD\u2010MND) in the Mayo Clinic Brain Bank.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that TDP\u201043 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in <jats:italic>APOE2<\/jats:italic> mice, with much milder or absent effects in <jats:italic>APOE3<\/jats:italic>, <jats:italic>APOE4<\/jats:italic>, or <jats:italic>Apoe<\/jats:italic>\u2010KO mice. In the motor cortex of the ALS and FTLD\u2010MND postmortem human brains, we found that the <jats:italic>APOE<\/jats:italic>2 allele was associated with more severe TDP\u201043\u2010positive dystrophic neurites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our data suggest a genotype\u2010specific effect of <jats:italic>APOE<\/jats:italic> on TDP\u201043 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with <jats:italic>APOE2<\/jats:italic>. ANN NEUROL 2023;93:830\u2013843<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26580","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T12:45:27Z","timestamp":1671713127000},"page":"830-843","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>APOE2<\/scp> Exacerbates <scp>TDP<\/scp>\u201043 Related Toxicity in the Absence of Alzheimer Pathology"],"prefix":"10.1002","volume":"93","author":[{"given":"Axel D.","family":"Meneses","sequence":"first","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida"},{"name":"Clinical and Translational Science Graduate Program Mayo Clinic  Jacksonville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville 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