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Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer\u2019s disease (AD) patients, in addition to amyloid-\u03b2 and \u03c4 protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and\/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43<jats:sup>409\/410<\/jats:sup>, but also for pTDP-43 phosphorylated at serines 403\/404 (pTDP-43<jats:sup>403\/404<\/jats:sup>) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as AD<jats:sup>TDP\u2009+\u2009FL<\/jats:sup> because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409\/410 (pTDP-43<jats:sup>409<\/jats:sup>, pTDP-43<jats:sup>409\/410<\/jats:sup>). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as AD<jats:sup>TDP\u2009+\u2009CTF<\/jats:sup>. Ten AD cases did not contain any TDP-43 pathology and were referred to as AD<jats:sup>TDP-<\/jats:sup>. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of AD<jats:sup>TDP\u2009+\u2009CTF<\/jats:sup> cases, 63,6% of AD<jats:sup>TDP\u2009+\u2009FL<\/jats:sup> and 100% of the AD<jats:sup>TDP-<\/jats:sup> cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of AD<jats:sup>TDP\u2009+\u2009FL<\/jats:sup>, in 16,6% of the AD<jats:sup>TDP\u2009+\u2009CTF<\/jats:sup>, and in none of the AD<jats:sup>TDP-<\/jats:sup> cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from AD<jats:sup>TDP-<\/jats:sup> to AD<jats:sup>TDP\u2009+\u2009CTF<\/jats:sup> and AD<jats:sup>TDP\u2009+\u2009FL<\/jats:sup> with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in AD<jats:sup>TDP\u2009+\u2009FL<\/jats:sup> cases.<\/jats:p>","DOI":"10.1186\/s40478-020-00934-5","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T09:03:49Z","timestamp":1588151029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Distinct molecular patterns of TDP-43 pathology in Alzheimer\u2019s disease: relationship with clinical phenotypes"],"prefix":"10.1186","volume":"8","author":[{"given":"Sandra O.","family":"Tom\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Vandenberghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Ospitalieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelien","family":"Van Schoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Tousseyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A. 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Ethical approval for the use of cases was granted by the ethical committee of Ulm University (Germany) and UZ\/KU-Leuven ethical committee (Belgium). This study covering the retrospective analysis of samples and data was approved by the UZ\/KU-Leuven ethical committee (S-59295) (Belgium).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable for this study, which did not use person\u2019s data. Only anonymized or pseudonymized data were processed.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"DRT received speaker honorary from Novartis Pharma AG (Switzerland) and Biogen (USA), travel reimbursement from GE-Healthcare (UK) and UCB (Belgium) and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium).CAFvA received honoraria from serving on the scientific advisory board of Nutricia GmbH (2014), Roche (2018) and Hong Kong University Research council (2014) and has received funding for travel and speaker honoraria from Nutricia GmbH (2014\u20132015), Lilly Deutschland GmbH (2013\u20132016), Desitin Arzneimittel GmbH (2014), Biogen (2016\u20132018), Roche (2017\u20132019) and Dr. Willmar Schwabe GmbH &Co. 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