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of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. Advances in fluid and imaging biomarkers are transforming dementia diagnosis but have not been systematically applied to individuals previously exposed to head impacts during rugby participation.<\/jats:p>\n                  <jats:p>We used biomarkers, including those with sensitivity and specificity for early Alzheimer's pathology to explore neurodegenerative risk in mid-life elite retired rugby players with significant repetitive head impact exposure. Plasma neurofilament light, glial fibrillary acid protein, amyloid-\u03b2 (A\u03b2)42, A\u03b240 and phospho-tau217 were quantified using ultrasensitive single molecule array digital enzyme-linked immunosorbent assay (SiMoA) in former elite rugby players as well as age\/sex-matched unexposed controls. 3\u2005T MRI and neuropsychology assessments were performed, with National Institute for Neurological Disorders and Stroke criteria used to ascertain the presence of traumatic encephalopathy syndrome. Regression models were used to relate plasma\/imaging biomarkers to clinical phenotype. Individual-levels analyses were performed for fluid and imaging metrics, based on control biomarker distributions. Biomarker data from two aligned un-exposed Alzheimer's cohorts were included to contextualize our findings.<\/jats:p>\n                  <jats:p>Two hundred ex-rugby players (median age 44\u2005years, 90% males) and 33 unexposed controls were assessed. Twenty-four (12%) ex-players fulfilled criteria for traumatic encephalopathy syndrome but none had dementia. Plasma phospho-tau217 concentrations were 17.6% higher in ex-rugby players than controls (95% confidence interval 3.7\u201333.3, P = 0.047). A total of 46 (23.1%) ex-players had elevated phospho-tau217 at the individual level; as did 18 (9.0%) players in relation to raised plasma neurofilament light. Ex-players\u2019 concentrations were lower than in unexposed adults with late onset Alzheimer's disease (n = 69). Ex-players also showed significantly reduced volumes in the frontal\/cingulate cortex on voxel-based morphometry at the group level; with reduced white matter and lower hippocampal volume associated with longer career durations within ex-players. Trauma-associated white matter changes measured with diffusion tensor imaging were uncommon in ex-players (4.6%). Traumatic encephalopathy syndrome was significantly more common in ex-players with elevated phospho-tau217, while those with raised plasma neurofilament light had significantly more anxiety and depressive symptoms. Frontal brain volumes correlated negatively with neurofilament light (r = \u22120.21, P = 0.010), and hippocampal volumes correlated negatively with phospho-tau217 (r = \u22120.19, P = 0.024).<\/jats:p>\n                  <jats:p>Elite rugby participation is associated with abnormal fluid and neuroimaging neurodegeneration biomarkers in mid-life. These include elevated phospho-tau217, which may indicate amyloid-dependent tau pathology. The results provide support for using state-of-the-art neurodegenerative biomarkers in the evaluation of long-term effects of sports head impact exposure.<\/jats:p>","DOI":"10.1093\/brain\/awaf152","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T07:54:57Z","timestamp":1749628497000},"page":"2684-2697","source":"Crossref","is-referenced-by-count":14,"title":["Biomarker evidence of neurodegeneration in mid-life former rugby players"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0183-3368","authenticated-orcid":false,"given":"Neil S N","family":"Graham","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Centre for Injury Studies, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl A","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Centre for Injury Studies, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-6418","authenticated-orcid":false,"given":"Jessica","family":"Hain","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Rooney","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Institute of Sport, Exercise and Health (ISEH), University College London , London W1T 7HA ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lee","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Institute of Sport, Exercise and Health (ISEH), University College London , London W1T 7HA ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Del Giovane","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-4220","authenticated-orcid":false,"given":"Thomas","family":"Parker","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Centre for Injury Studies, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew G","family":"Wilson","sequence":"additional","affiliation":[{"name":"Institute of Sport, Exercise and Health (ISEH), University College London , London W1T 7HA ,","place":["UK"]},{"name":"HCA Healthcare, HCA Healthcare Research Institute , London W1T 7HA ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1897-0780","authenticated-orcid":false,"given":"Paresh","family":"Malhotra","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C B","family":"David","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Kolanko","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maneesh","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Imaging, Imperial College Healthcare NHS Trust , London W6 8RF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Veleva","sequence":"additional","affiliation":[{"name":"UCL, UK Dementia Research Institute at University College London , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"Swann","sequence":"additional","affiliation":[{"name":"UCL, UK Dementia Research Institute at University College London , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Heslegrave","sequence":"additional","affiliation":[{"name":"UCL, UK Dementia Research Institute at University College London , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"UCL, UK Dementia Research Institute at University College London , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal 413 90 ,","place":["Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal 413 45 ,","place":["Sweden"]},{"name":"Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay , 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":"Daniel","family":"Friedland","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Sylvester","sequence":"additional","affiliation":[{"name":"Institute of Sport, Exercise and Health (ISEH), University College London , London W1T 7HA ,","place":["UK"]},{"name":"Acute Stroke and Brain Injury Unit, National Hospital for Neurology and Neurosurgery, Queen Square , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J","family":"Sharp","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Centre for Care Research & Technology Centre, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Department of Brain Sciences, Imperial College London , London W12 0BZ ,","place":["UK"]},{"name":"Centre for Injury Studies, Imperial College London , London W12 0BZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"2025080112525125600_awaf152-B1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S1474-4422(17)30279-X","article-title":"The chronic and evolving neurological consequences of traumatic brain injury","volume":"16","author":"Wilson","year":"2017","journal-title":"Lancet Neurol"},{"key":"2025080112525125600_awaf152-B2","doi-asserted-by":"crossref","first-page":"e740","DOI":"10.1212\/WNL.0000000000207501","article-title":"Long-term multi-domain 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