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Short report
Alzheimer’s disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI
  1. Neil Graham1,2,
  2. Karl Zimmerman1,2,
  3. Amanda J Heslegrave3,
  4. Ashvini Keshavan4,
  5. Federico Moro5,6,
  6. Samia Abed-Maillard7,
  7. Adriano Bernini8,
  8. Vincent Dunet9,
  9. Elena Garbero10,
  10. Giovanni Nattino10,
  11. Arturo Chieregato11,
  12. Enrico Fainardi12,
  13. Camelia Baciu11,
  14. Primoz Gradisek13,
  15. Sandra Magnoni14,
  16. Mauro Oddo7,15,
  17. Guido Bertolini10,
  18. Jonathan M Schott3,16,
  19. Henrik Zetterberg3,17,
  20. David Sharp1,2
  1. 1 Brain Sciences, Imperial College London, London, UK
  2. 2 UK Dementia Research Institute Centre for Care Research and Technology, Imperial College London, London, UK
  3. 3 UK Dementia Research Institute, University College London, London, UK
  4. 4 Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK
  5. 5 Laboratory of Acute Brain Injury and Neuroprotection, Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
  6. 6 Dipartimento di Anestesia e Rianimazione, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
  7. 7 Neuroscience Critical Care Research Group, Department of Intensive Care Medicine, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  8. 8 Department of Clinical Neurosciences, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  9. 9 Department of Medical Radiology, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  10. 10 Laboratory of Clinical Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Italy
  11. 11 Terapia Intensiva ad indirizzo Neurologico & Neurochirurgico, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
  12. 12 Department of Experimental and Clinical Sciences, Careggi University Hospital and University of Firenze, Florence, Italy
  13. 13 Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Center, Ljubljana, Slovenia
  14. 14 Department of Anesthesia and Intensive Care, Santa Chiara Hospital, Trento, Italy
  15. 15 Directorate for Innovation and Clinical Research, CHUV Lausanne University Hospital, Lausanne, Switzerland
  16. 16 Dementia Research Centre and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
  17. 17 Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  1. Correspondence to Dr David Sharp, Department of Brain Sciences, Imperial College London, London, SW7 2BX, UK;{at}


Background Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer’s disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer’s disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy.

Methods Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer’s disease, with healthy controls.

Results Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer’s disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates.

Conclusions Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.


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Traumatic brain injury (TBI) is common occurrence and an environmental risk factor for dementia. A range of pathologies are described postinjury including the tauopathies Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE),1 which form part of the broader complex constellation of postinjury pathologies and has been termed traumatic brain injury-related neurodegeneration (TReND) (online supplemental ref).

Supplemental material

A key question is how acute traumatic elevations of τ relate to progressive neurodegeneration. This is potentially mechanistically important as abnormal τ may cause neurodegeneration through prion-like proteopathic seeding. Total τ (t-tau) is increased more than one hundred-fold after moderate-to-severe TBI in brain extracellular fluid, and plasma t-tau predicts neurodegeneration. However, in contrast to the axonal degeneration marker neurofilament light (NfL) and astroglial marker glial fibrillar acidic protein (GFAP), t-tau rapidly normalises.2 Advanced biomarker assays now allow investigation of links between TBI and dementia. In AD, τ phosphorylated at threonine 181 (p-tau181) correlates with neuropathology,3 and is being incorporated clinically. P-tau181 has not been investigated after moderate-to-severe TBI.

We assessed plasma P-tau181 in a subset of the BIO-AX-TBI cohort of moderate-to-severe TBI (defined using the Mayo classification, see online supplemental file 1), healthy controls and AD patients, comparing blood biomarker concentrations to MRI measures of neurodegeneration in the TBI group. We have previously described the cohort and characterised trends of NfL, t-tau, neuronal marker ubiquitin C-terminal hydrolase L1 (UCH-L1) and GFAP. Hence, we were able to directly compare these markers with P-tau181 .2 We hypothesised that: (1) p-tau181 would increase early post-TBI, (2) remain elevated at 1 year and (3) predict brain atrophy.


P-tau181 was quantified over 1 year in 42 patients after moderate-to-severe TBI, aged 48.7 years (mean, SD 15.6) with 76.2% male (online supplemental table 1). The lowest Glasgow Coma Scale was 3–8 in 26.8%, 9–13 in 39.0% and 14–15 in 34.1% (unknown in n=1). Diffuse injury was present on CT in 4.8%, with contusions/intraparenchymal haemorrhage in 47.6%, subdural haematoma in 57.1%, and extradural haematoma in 14.3%. This group had less severe injuries that the broader BIO-AX-TBI cohort previously reported, indicated by lower peak 10-day injury biomarker concentrations (all p<0.05, except NfL).2 A group of male healthy controls underwent aligned p-tau181 assessment (mean 45.9 years, SD 3.2). Thirty-one patients with AD were also assessed (63.7 years, SD 6.5, 48.4% male) and 14 non-AD controls (mean 60.6 years, SD 6.5, 71.4% male). Age and sex were included as confounders.

Median plasma p-tau181 at 2.7 days (SD 2.8) post-TBI was 1.5 pg/mL (IQR 1.7) and did not differ significantly from healthy volunteers (median 1.5 pg/mL, IQR 1.9) (see figure 1; online supplemental table 2). P-tau181 concentrations were stable in the year after injury: day 6.3 (SD 2.4) 1.5 pg/mL (IQR 1.0); day 30.0 (SD 12.1) 1.3 pg/mL (IQR 0.8); 6 months 1.4 pg/mL (IQR 0.7) and 1 year 1.5 pg/mL (IQR 0.5). There was no significant longitudinal change. In contrast, reductions were seen in t-tau, GFAP, NfL and UCH-L1 as previously reported (all p<0.001).2

Figure 1

Longitudinal fluid biomarker trajectories after moderate-to-severe TBI, healthy volunteers and Alzheimer’s disease. Fluid biomarkers in healthy volunteers, longitudinally in patients following TBI, people with AD and non-AD healthy controls (non-AD controls). Boxplots show median and quartiles (hinges), with whiskers extending upto 1.5 times the IQR. Individual data points are shown and connected by lines indicating within-subject trajectories. (A) shows p-tau181; (B) shows total τ (t-tau), neurofilament light (NfL), ubiquitin c-terminal hydrolase L1 (UCH-L1) and glial fibrillar acidic protein (GFAP). AD, Alzheimer’s disease; TBI, traumatic brain injury.

There was no significant correlation of p-tau181 measured subacutely and grey matter atrophy measured at 6 months, nor between concentrations within 6 months and white matter atrophy at 6–12 months. As previously shown in the wider cohort,2 hyperacute t-tau predicted grey matter atrophy (p=0.046; adjusted R2=0.12), and subacute plasma NfL predicted white matter atrophy (p=0.004, R2=0.20).2 P-tau181 was significantly raised in AD (2.0 times (1.5–2.7) higher, p<0.001) versus non-AD controls.


Plasma p-tau181 was not elevated after moderate-to-severe TBI and concentrations did not vary significantly over 1 year. This contrasts with our previous findings in other markers t-tau, NfL, GFAP and UCH-L1, which showed substantial elevations.2 Unlike plasma t-tau and NfL, we found no correlation of p-tau181 at any time point and brain atrophy, a measure of neurodegeneration.

P-tau181 is a neuropathologically validated in vivo marker of amyloid-induced τ phosphorylation in AD.3 Given the presence of amyloid and τ pathologies post-TBI, there is interest in whether TBI may trigger neurodegeneration through mechanisms similar to AD, and whether this is reflected in AD-specific blood biomarkers. AD patients showed substantial p-tau181 elevations, demonstrating the assay’s sensitivity, but this was not seen post-TBI. The lack of p-tau181 elevation at 1-year contrasts with neurodegeneration marker NfL and astroglial marker GFAP, both of which remained chronically elevated, as previously reported.2 It is possible that phosphorylated τ accumulates as a late consequence of TBI and we would not have identified this in our 1-year follow-up period. Post-traumatic neurodegeneration is likely to be dynamic over time and a specific temporal pattern of plasma p-tau isoform changes, as seen in AD where plasma p-tau231 precedes p-tau181 positivity, with both markers well correlated with τ PET.4 Very long-term follow-up incorporating comprehensive longitudinal fluid biomarker assessment, brain volumetry and molecular imaging would likely be highly informative.

It is possible that other blood markers may be more specific to post-traumatic neurodegeneration. For example, postmortem work suggests that p-tau202 may have greatest specificity for CTE. This has yet to be assessed clinically as there is not currently a reliable assay to do so at scale. In addition, brain derived τ shows promise as a marker, correlating more closely with CSF τ and neurofibrillary tangle burden in AD better than t-tau (online supplemental ref).

There are several potential limitations. Relatively few patients were sampled <24 hours after injury, hence we may have missed an early peak in p-tau181 as previously seen using a different assay-type quantifying p-tau231.5 Second, the use of p-tau181 controls analysed separately from TBI patients may introduce bias: however, we feel this is unlikely due to good assay performance, large numbers, and lack of longitudinal injury-associated change. Last, TBI and young controls were not well sex-matched, though this was included in statistical models.

In conclusion, plasma p-tau181 was not increased over 1 year after moderate-to-severe TBI and was not associated with neurodegeneration. P-tau181 dynamics were not only distinct from t-tau but differed from other biomarkers NfL, GFAP and UCH-L1. This suggests that p-tau181 does not contribute to progressive neurodegeneration commonly seen after TBI, at least in the first year.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by COAT study (TBI patients): Camberwell and St Giles REC; ref 17/LO/2066 CSF study (AD patients 12/3044): Queen Square Research Ethics Committee; ref 12_LO_1504ADVANCE study (controls): Ministry of Defence Research Ethics Committee (MODREC); ref 20220405-2126MODREC22. Participants gave informed consent to participate in the study before taking part.


Supplementary materials

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  • Twitter @nsngraham, @jmschott, @neurosharp

  • Contributors DS, HZ, NG, KZ, SA-M, MO, PG and GB were involved in the design and conception of the study. All authors were involved in data collection, collation and quality control. The first draft was prepared by NG, and DS revised initial iterations. All authors reviewed and approved the final version of the manuscript.

  • Funding Core funds for the BIO-AX-TBI project were from the ERA-NET NEURON Cofund (MR/R004528/1), a part of the European Research Projects on External Insults to the Nervous System call, within the Horizon 2020 funding framework, (PIs: DS, HZ, MO, GB and SM). Other sources included: Alzheimer’s Research UK Clinical Research Fellowship and National Institute for Health Research (UK) Academic Clinical Lectureship (NG), UK Dementia Research Institute (DRI) Care Research and Technology Centre (NG, DS and KZ), National Institute of Health Research (NIHR) Professorship (NIHR-RP-011-048) (DS), the NIHR Clinical Research Facility and Biomedical Research Centre (BRC) at Imperial College Healthcare NHS Trust (NG, DS), Medical Research Council Clinician Scientist Fellowship (DS). Plasma p-tau181 analysis at UCL was funded by an Alzheimer’s Research UK Network Pump Priming grant (AK) AK and JMS acknowledge the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Weston Brain Institute (UB170045) and the Alzheimer’s Association. JMS acknowledges the support of the Wolfson Foundation, ARUK (ARUK-PG2017-1946), Brain Research UK (UCC14191), Medical Research Council, British Heart Foundation and European Union’s Horizon 2020 research and innovation programme (Grant 666992). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694) and the UK Dementia Research Institute at UCL (UKDRI-1003). MO is supported by the Swiss National Science Foundation (nos. 31NE30_173675 and 32003B_188501).

  • Competing interests HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). MO received research support and speaker fees from Neuroptics, USA, unrelated to the present work, and is member of the Scientific Advisory Board of Neuroptics. DS serves on the concussion advisory board of the UK Rugby Football Union, and undertakes clinical private practice including medicolegal assessments.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.