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Genome-wide association studies revealed that the \u03b54 allele of the apolipoprotein E (<jats:italic>APOE4<\/jats:italic>) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-\u03b2 (A\u03b2) and \u03b1-SYN pathogenesis. How APOE4 modulates \u03b1-SYN aggregation in AD is unclear. In this study, we aimed to determine how \u03b1-SYN is associated with AD-related pathology and how APOE4 impacts \u03b1-SYN seeding and toxicity. We measured \u03b1-SYN levels and their association with other established AD-related markers in brain samples from autopsy-confirmed AD patients (<jats:italic>N<\/jats:italic>\u2009=\u2009469), where 54% had concomitant LB pathology (AD\u2009+\u2009LB). We found significant correlations between the levels of \u03b1-SYN and those of A\u03b240, A\u03b242, tau and APOE, particularly in insoluble fractions of AD\u2009+\u2009LB. Using a real-time quaking-induced conversion (RT-QuIC) assay, we measured the seeding activity of soluble \u03b1-SYN and found that \u03b1-SYN seeding was exacerbated by APOE4 in the AD cohort, as well as a small cohort of autopsy-confirmed LBD brains with minimal Alzheimer type pathology. We further fractionated the soluble AD brain lysates by size exclusion chromatography (SEC) ran on fast protein liquid chromatography (FPLC) and identified the \u03b1-SYN species (~\u200996\u00a0kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified \u03b1-SYN aggregates from AD\u2009+\u2009LB brain of patients with <jats:italic>APOE4<\/jats:italic> were highly toxic to neurons, whereas the same amount of \u03b1-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates \u03b1-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects \u03b1-SYN pathogenesis in AD.<\/jats:p>","DOI":"10.1007\/s00401-022-02421-8","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T15:09:31Z","timestamp":1650985771000},"page":"641-662","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["APOE4 exacerbates \u03b1-synuclein seeding activity and contributes to neurotoxicity in Alzheimer\u2019s disease with Lewy body pathology"],"prefix":"10.1007","volume":"143","author":[{"given":"Yunjung","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berkiye","family":"Sonoustoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveen Chandra","family":"Kondru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka A.","family":"Martens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadafumi C.","family":"Ikezu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy D.","family":"Burgess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilyn","family":"Amerna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"O\u2019Leary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"DeTure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"McLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8648-9422","authenticated-orcid":false,"given":"Na","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"key":"2421_CR1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.4161\/idp.26255","volume":"1","author":"TR Alderson","year":"2013","unstructured":"Alderson TR, Markley JL (2013) Biophysical characterization of alpha-synuclein and its controversial structure. 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