{"doi":"10.1093/brain/awac407","title":"Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration","abstract":"Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's 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. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' 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. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 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's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's 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 = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, 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's 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's 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. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.","journal":"Brain","year":2022,"id":232210,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":239,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":843049,"name":"Michael Turton","orcid":null,"position":1,"is_corresponding":false},{"id":841866,"name":"Przemysław R. Kac","orcid":"0000-0001-5083-0924","position":2,"is_corresponding":false},{"id":411682,"name":"Denis S. Smirnov","orcid":"0000-0002-9768-313X","position":3,"is_corresponding":false},{"id":241670,"name":"Enrico Premi","orcid":"0000-0002-4342-6963","position":4,"is_corresponding":false},{"id":448751,"name":"Roberta Ghidoni","orcid":"0000-0002-7691-1957","position":5,"is_corresponding":false},{"id":448740,"name":"Luisa Benussi","orcid":"0000-0003-2836-8141","position":6,"is_corresponding":false},{"id":626049,"name":"Valentina Cantoni","orcid":"0000-0002-9933-5649","position":7,"is_corresponding":false},{"id":841867,"name":"Claudia Saraceno","orcid":"0000-0001-8618-4282","position":8,"is_corresponding":false},{"id":841868,"name":"Jasmine Rivolta","orcid":"0009-0002-1614-4861","position":9,"is_corresponding":false},{"id":241104,"name":"Nicholas J. Ashton","orcid":"0000-0002-3579-8804","position":10,"is_corresponding":false},{"id":65560,"name":"Barbara Borroni","orcid":"0000-0001-9340-9814","position":11,"is_corresponding":false},{"id":108599,"name":"Douglas Galasko","orcid":"0000-0001-6195-3241","position":12,"is_corresponding":false},{"id":843050,"name":"Peter Harrison","orcid":null,"position":13,"is_corresponding":false},{"id":27601,"name":"Henrik Zetterberg","orcid":"0000-0003-3930-4354","position":14,"is_corresponding":false},{"id":27600,"name":"Kaj Blennow","orcid":"0000-0002-1890-4193","position":15,"is_corresponding":false},{"id":241105,"name":"Thomas K. Karikari","orcid":"0000-0003-1422-4358","position":16,"is_corresponding":false},{"id":839573,"name":"Fernando González‐Ortiz","orcid":"0000-0001-7897-9456","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T00:21:12.348693Z","pmid":"36572122","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}