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However, it remains largely unclear how distinctive Alzheimer\u2019s disease tau seeds (i.e. 3R\/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R\/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer\u2019s-related tau accumulation anywhere in the brain. In later stages of AD, 3R\/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer\u2019s tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer\u2019s cases. \u03b1-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of \u03b1-synuclein seeds in some Alzheimer\u2019s disease and primary tauopathy cases. Our analysis indicates that 3R\/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer\u2019s disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R\/4R tau seeds are elevated in females compared to males at high (\u2265\u2009IV) Braak stages. This study suggests 3R\/4R tau seeds are widespread even prior to the earliest stages of Alzheimer\u2019s disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.<\/jats:p>","DOI":"10.1007\/s00401-023-02574-0","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T06:02:17Z","timestamp":1683525737000},"page":"31-50","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Tau seeds occur before earliest Alzheimer\u2019s changes and are prevalent across neurodegenerative diseases"],"prefix":"10.1007","volume":"146","author":[{"given":"Matteo","family":"Manca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi G.","family":"Standke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle F.","family":"Browne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikayla L.","family":"Huntley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia R.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina D.","family":"Orr\u00fa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Hughson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongya","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis","family":"Tatsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongwei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Hiniker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Coughlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Galasko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8477-0894","authenticated-orcid":false,"given":"Allison","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"key":"2574_CR1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat8462","author":"A Aoyagi","year":"2019","unstructured":"Aoyagi A, Condello C, Stohr J, Yue W, Rivera BM, Lee JC et al (2019) Abeta and tau prion-like activities decline with longevity in the Alzheimer\u2019s disease human brain. 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