Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players
- PMID: 41047224
- DOI: 10.1136/jnnp-2025-336593
Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players
Abstract
Background: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment.
Methods: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES).
Results: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau181 (p-tau181). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES.
Conclusions: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-181 more so than p-tau217 points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.
Keywords: DEMENTIA; HEAD INJURY; NEUROBIOLOGY; TRAUMATIC BRAIN INJURY.
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.
Conflict of interest statement
Competing interests: The primary study funders (FA/RFU/PRL) did not have a role in the collection, analysis or interpretation of the data nor the writing of the report or in the decision to submit the paper for publication. When the clinic and aligned cohort were originally established, the primary funders did, in conjunction with the authors, determine the eligibility criteria which are reflected in the inclusion criteria for the study (eg, ex-player age range and level of elite play). DJS has received support of blood biomarker analysis (unrelated to this paper) by Quanterix and previously from Alamar. DJS and RJS participate in an expert panel advising the English Rugby Football Union on concussion and related issues. DJS has received an honorarium from the Rugby Football Union for his participation, which has been used for research purposes. RJS acts as an independent concussion expert for World Rugby and receives payment for providing independent clinical care for professional players following head injuries. DJS and RS have received complementary tickets to international rugby matches paid for by the Rugby Football Union. ISEH invoices the Rugby Football Union for the number of ex-players seen in clinic per quarter. In turn, DJS, RS, DF and MP receive pass through payment from ISEH for the provision of private clinical services. ISEH receives funding from the RFU and FA to employ NG, EJR and YL for the provision of research services. Imperial College London receive funding from the RFU and FA to support the employment of JAH, KAZ and MDG for the provision of research services. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, 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 Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk 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).
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