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However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer\u2019s disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources.<\/jats:p>\n                  <jats:p>We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed \u2018big tau\u2019 isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts.<\/jats:p>\n                  <jats:p>In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P &amp;lt; 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer\u2019s disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer\u2019s disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52\u20130.67, P = 0.003), but not neurofilament light (rho = \u22120.14\u20130.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer\u2019s disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma\/serum brain-derived tau correlated with neurofilament light only in Alzheimer\u2019s disease but not in the other neurodegenerative diseases. Across cohorts, plasma\/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function.<\/jats:p>\n                  <jats:p>Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer\u2019s disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer\u2019s disease-dependent neurodegenerative processes for clinical and research purposes.<\/jats:p>","DOI":"10.1093\/brain\/awac407","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T08:21:19Z","timestamp":1667809279000},"page":"1152-1165","source":"Crossref","is-referenced-by-count":255,"title":["Brain-derived tau: a novel blood-based biomarker for Alzheimer\u2019s disease-type neurodegeneration"],"prefix":"10.1093","volume":"146","author":[{"given":"Fernando","family":"Gonzalez-Ortiz","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg 405 30 , 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University of Brescia , Brescia, BS 25121 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Ghidoni","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli , Brescia 25121 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Benussi","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli , Brescia 25121 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Cantoni","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia , Brescia, BS 25121 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Saraceno","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS 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Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation , London, SE5 8AF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9340-9814","authenticated-orcid":false,"given":"Barbara","family":"Borroni","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia , Brescia, BS 25121 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Galasko","sequence":"additional","affiliation":[{"name":"University of California, San Diego and Shiely-Marcos Alzheimer\u2019s Disease Research Center , La Jolla, CA 92037 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Harrison","sequence":"additional","affiliation":[{"name":"Bioventix Plc, Romans Business Park , Farnham, Surrey GU9 7SX , 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