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However, their true diagnostic performance, relative to conventional CSF and plasma phosphorylated tau assays, remains uncharacterized. The objective was to compare the diagnostic performance of brain-derived and conventional phosphorylated tau assays across multiple analytes (phosphorylated tau 181, phosphorylated tau 217, phosphorylated tau 231) in CSF and plasma, and to examine biomarker differences across amyloid-\u03b2 status and cognitive groups. This study included 1098 participants with amyloid-PET imaging and CSF samples from the Alzheimer\u2019s Disease Neuroimaging Initiative, and a subset of 925 individuals with plasma samples. Diagnostic performance of brain-derived and conventional phosphorylated tau assays was assessed by receiver operating characteristic curves, with calculation of area under the curve, sensitivity, specificity and optimal cutpoints. Associations with amyloid-\u03b2 burden were evaluated using Spearman correlations, and fold-changes between amyloid-PET-positive and amyloid-PET-negative participants were computed in cognitively unimpaired and cognitively impaired subgroups with 95% confidence intervals from 2000 bootstrap resamples. Brain-derived phosphorylated tau assays showed significantly higher diagnostic performance than conventional phosphorylated tau assays at the same phosphorylation site in both CSF and plasma in the overall sample and in cognitively impaired individuals, except for CSF phosphorylated tau 217. While CSF brain-derived phosphorylated tau correlations with amyloid-PET were similar to conventional CSF assays, pairwise comparisons using DeLong\u2019s test revealed significantly higher diagnostic accuracy for brain-derived assays. Receiver operating characteristic performance was generally better in cognitively impaired participants than in cognitively unimpaired participants. Additionally, using a three-range method with cutpoints corresponding to 90% sensitivity and 90% specificity, plasma brain-derived phosphorylated tau 181, phosphorylated tau 217 and brain-derived phosphorylated tau 217 had &amp;lt;20% of participants in the intermediate range overall and in cognitively impaired individuals. In summary, brain-derived phosphorylated tau assays improve detection of amyloid-\u03b2 positivity relative to conventional assays, especially in plasma, and provide robust differentiation of amyloid-PET-positive and amyloid-PET-negative participants. If these findings are confirmed using fully automated diagnostic platforms that are intended for use in clinical settings, brain-derived phosphorylated tau assays may support future blood-based biomarker triage workflows for identifying Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag376","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:37:01Z","timestamp":1791286621000},"source":"Crossref","is-referenced-by-count":0,"title":["Comparison of brain-derived versus conventional pTau biomarkers in CSF and plasma for detecting Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5593-7717","authenticated-orcid":false,"given":"Lydia","family":"Trudel","sequence":"first","affiliation":[{"name":"Translational Neuroimaging Laboratory, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7826-4781","authenticated-orcid":false,"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8434-9407","authenticated-orcid":false,"given":"Valentina","family":"Ghisays","sequence":"additional","affiliation":[{"name":"Banner Alzheimer\u2019s Institute , Phoenix, AZ 85006 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur C","family":"Macedo","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8953-1542","authenticated-orcid":false,"given":"Paolo","family":"Vitali","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L","family":"Benedet","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6ldnal, 413 90 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6ldnal, 413 90 ,","place":["Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Gothenburg 413 45 ,","place":["Sweden"]},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"UK Dementia Research Institute at UCL , London NW1 3BT ,","place":["UK"]},{"name":"Hong Kong Center for Neurodegenerative Diseases , Hong Kong ,","place":["China"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Su","sequence":"additional","affiliation":[{"name":"Banner Alzheimer\u2019s Institute , Phoenix, AZ 85006 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alpana","family":"Singh","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute , Sun City, AZ 85351 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tain\u00e1","family":"Marques","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute , Sun City, AZ 85351 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa N","family":"Denkinger","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute , Sun City, AZ 85351 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas T","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan I","family":"Levey","sequence":"additional","affiliation":[{"name":"Goizueta Alzheimer\u2019s Disease Research Center, Emory University School of Medicine , Atlanta, GA 30329 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W","family":"Weiner","sequence":"additional","affiliation":[{"name":"Northern California Institute for Research and Education (NCIRE) Center for Imaging of Neurodegenerative Diseases, , San Francisco, CA 94121 ,","place":["USA"]},{"name":"Departments of Radiology, Medicine, Psychiatry, & Neurology, University of California San Francisco , San Francisco, CA 94121 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendall","family":"Van Keuren-Jensen","sequence":"additional","affiliation":[{"name":"Neurogenomics Division, TGen , Phoenix, AZ 85004 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M","family":"Reiman","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute , Sun City, AZ 85351 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Ashton","sequence":"additional","affiliation":[{"name":"Banner Alzheimer\u2019s Institute , Phoenix, AZ 85006 ,","place":["USA"]},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6ldnal, 413 90 ,","place":["Sweden"]},{"name":"Banner Sun Health Research Institute , Sun City, AZ 85351 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-1376","authenticated-orcid":false,"given":"Pedro","family":"Rosa-Neto","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Montreal Neurological Institute , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University , Montreal, Quebec H3A 2B4 ,","place":["Canada"]},{"name":"Peter O\u2019Donnell Jr. Brain Institute (OBI), University of Texas Southwestern Medical Centre (UTSW) , Dallas, TX 75235 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"issue":"15","key":"2026101504073462200_fcag376-B1","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1001\/jama.2024.13855","article-title":"Blood biomarkers to detect Alzheimer disease in primary care and secondary care","volume":"332","author":"Palmqvist","year":"2024","journal-title":"JAMA"},{"issue":"5","key":"2026101504073462200_fcag376-B2","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/S1474-4422(20)30071-5","article-title":"Blood phosphorylated tau 181 as a biomarker for Alzheimer\u2019s disease: A diagnostic performance and prediction modelling study using data from four prospective cohorts","volume":"19","author":"Karikari","year":"2020","journal-title":"Lancet 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