Plasma eMTBR-tau as a robust biomarker for Alzheimer’s disease tangle pathology up to 10 years before death
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimer’s disease prognosis, diagnosis and monitoring. Here, we show that a blood-based immunoassay for an endogenously-cleaved “eMTBR-tau” fragment of tau protein is strongly associated with autopsy-diagnosed Alzheimer neuropathologic change (ADNC) and predominantly reflects the burden and anatomical progression of tangle pathology but not amyloid plaque load despite being most elevated in amyloid-positive symptomatic individuals. Plasma eMTBR-tau was significantly more accurate than plasma p-tau217 in classifying Braak staging and ADNC statuses at autopsy. Importantly, neuropathologic classification by plasma eMTBR-tau remained high (AUC=0.91-0.95) even when increasing intervals between blood collection and death up to a decade, while maintaining superior sensitivity and specificity over p-tau217. Higher baseline plasma eMTBR-tau was associated with worse cognition cross-sectionally and longitudinally predicted faster worsening. These results were replicated in a living cohort with in vivo tangle and plaque neuroimaging. Plasma eMTBR-tau concordance with tau neuroimaging was up to 94%, suggesting surrogacy. Together, plasma eMTBR-tau captures biological signatures of Braak staging and ADNC over a prolonged pre-mortem window, highlighting potential for early disease detection, biological staging, prognosis and therapeutic development.
Source: medRxiv
Institutions: University of Pittsburgh, University of Pittsburgh Medical Center, Mass General Brigham, Geriatric Research Education and Clinical Center, University of Wisconsin–Madison, Sahlgrenska University Hospital, UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, University of Gothenburg
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Defense, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, University of Pittsburgh, Stiftelsen för Gamla Tjänarinnor, National Institute for Health and Care Research, University College London, European Commission, Hjärnfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, UK Dementia Research Institute, National Institutes of Health, HORIZON EUROPE Framework Programme, National Institute on Aging, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke
Awards: G1057200632, BRAIN RISK ASSESSMENT FOR INDIVIDUAL NEUROLOGICAL (BRAIN) HEALTH: UNDERSTANDING/PREVENTING CONSEQUENCES FROM REPETITIVE MTBI AND HEAD IMPACT EXPOSURES, Genetic Architecture of Alzheimer’s disease Proteinopathies, G1451607819, G150733400, G1546555014, G1551449788, G1588116593, G1710774808, G1771944843, G1833008592, G1928552717, G196098375, G201353144, G2057385626, G2081597990, The role of astrogliosis in aging and the pathological and clinical progression of Alzheimer's Disease, G2224941001, G2256555670, G237833635, G2442294994, G2475953241, G2543812357, Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease, G2712175038, G2799940023, G2801031301, G292763017, G3241251457, Fluid biomarkers for neurodegenerative dementias, Myosteatosis, Cognition and Blood Biomarkers of Alzheimer's Disease in Persons of African Ancestry, G3483586962, G3509189227, Neurobiology of Mild Cognitive Impairment in the Elderly, G3809224024, G3842727039, G3880778400, G3903502641, G4166693258, G4167621408, G4228906844, G4234328627, G4244943609, G4260843567, G4287829823, G4377393254, Search for the Alzheimers Genes, G4786159458, G4834651813, Risk Genes in Alzheimer's Disease, G506008078, G516766298, Fluid biomarkers for neurodegenerative dementias, G5576250680, G5712520100, G5989133034, G6054361981, CASCADE: CAuSe or Consequence in Alzheimer DiseasE?, G6158734006, G6207287561, G6252389079, G6289970089, G6544145387, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G6701856265, G6745400708, G691317373, G7075164165, G7293611571, G7907773732, G8077616060, G9000216768, G9000257646, G9000300274, Alzheimer Diagnosis in older Adults with Chronic Conditions ADACC Network, Examining the Persistence of Neurocognitive Benefits of Exercise, Mild Cognitive Impairment: A Prospective Community Study, Alzheimer Disease Research Center, Longitudinal multicenter head-to-head harmonization of tau PET tracers, Head-to-head comparisons of high-performance plasma phospho-tau epitopes for the detection of Alzheimer's disease, Plasma brain-derived tau: a novel Alzheimer’s disease-type neurodegeneration biomarker with potential to complete the AT(N) scheme in blood, The RAW Brain - The Effect of Rumination, Anxiety and Worry on Aging and Dementia Risk, Brain CHEC-AC (Brain and Cognitive Health Equity Campaign for Allegheny County), Analytical characterization and validation of blood-biomarkers for monitoring TBI evolution, Predictors of Altered CNS Structure, Function, and Connectomics in the Elderly using a Health Disparities Framework, Roles of Gray Matter Brain Aging and Small Vessel Disease in AD Pathophysiology
OpenAlex ID: W7220467007