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Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link.<\/jats:p>\n                  <jats:p>In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental animal epilepsy models to human epileptic syndromes. Seizure prevalence is evaluated across established primary and secondary tauopathies to understand the associated hyperexcitability phenotype. We discuss the use of neurophysiology, metabolic imaging and novel fluid biomarkers as non-invasive measures of potential underlying neurodegeneration in epilepsy. It may, for example, be that these can be combined with remote measures of cognition and other physiological parameters to provide accurate longitudinal monitoring of cognition and underlying pathology. We also explore clinical trials that have targeted pathological tau accumulation in neurodegenerative conditions and consider an ongoing clinical study with sodium selenate, an enhancer of protein phosphatase enzyme PP2A, in people with epilepsy. These efforts signify a novel disease-modifying era with treatments that reduce seizures and modify cognitive outcomes in people with epilepsy.<\/jats:p>\n                  <jats:p>Our analysis of the literature underscores the need for more in-depth characterization of tau pathology, at biochemical and structural levels in brain tissue and peripheral samples from people with epilepsy, as an important step to deciphering the role of tau in the pathogenesis of epilepsy and related disorders. Examining the relationships between tau pathology and cognitive impairment in those with epilepsy provides critical perspectives on potential causal tau pathomechanisms that may have important roles in epileptogenesis and dementia.<\/jats:p>","DOI":"10.1093\/brain\/awag108","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T12:45:15Z","timestamp":1774010715000},"page":"2250-2272","source":"Crossref","is-referenced-by-count":2,"title":["Tau pathology in epilepsy: emerging mechanisms and translational opportunities"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8948-4763","authenticated-orcid":false,"given":"Arjune","family":"Sen","sequence":"first","affiliation":[{"name":"Oxford Epilepsy Research Group, Nuffield Department of Clinical Neuroscience, University of Oxford , Oxford OX3 9DU ,","place":["UK"]},{"name":"Division of Clinical Neurology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford OX3 9DU ,","place":["UK"]},{"name":"Centre for Global Epilepsy, Wolfson College , Oxford OX2 6UD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin You","family":"Tai","sequence":"additional","affiliation":[{"name":"Oxford Epilepsy Research Group, Nuffield Department of Clinical Neuroscience, University of Oxford , Oxford OX3 9DU ,","place":["UK"]},{"name":"Division of Clinical Neurology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristea","family":"Galanopoulou","sequence":"additional","affiliation":[{"name":"Saul R, Korey Department of Neurology, Laboratory of Developmental Epilepsy, Isabelle Rapin Division of Child Neurology, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine , Bronx, NY 10461 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Thom","sequence":"additional","affiliation":[{"name":"Department of Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3542-3770","authenticated-orcid":false,"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1182-0907","authenticated-orcid":false,"given":"Lucy","family":"Vivash","sequence":"additional","affiliation":[{"name":"The Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, Victoria 3004 ,","place":["Australia"]},{"name":"Department of Neurology, Alfred Health , Melbourne, Victoria 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Hardmeier","sequence":"additional","affiliation":[{"name":"Department of Neurology, Epilepsy and Sleep Unit, Medical Faculty of the University of Basel, University Hospital Basel , Basel CH-4031 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Action","family":"Amos","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5836-622X","authenticated-orcid":false,"given":"Stephan","family":"Rueegg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Epilepsy and Sleep Unit, Medical Faculty of the University of Basel, University Hospital Basel , Basel CH-4031 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Koepp","sequence":"additional","affiliation":[{"name":"Department of Epilepsy, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaroslav","family":"Winter","sequence":"additional","affiliation":[{"name":"Department of Neurology, Saarland University Medical Center, University of Saarland , Homburg 66421 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Helmstaedter","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn , Bonn 53127 ,","place":["Germany"]},{"name":"National Center for Epilepsy, Oslo University Hospital , Oslo 0424 ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L","family":"Noebels","sequence":"additional","affiliation":[{"name":"Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilal A","family":"Lashuel","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Chemical Biology of Neurodegeneration, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne , Lausanne 1015 ,","place":["Switzerland"]},{"name":"Weill Cornell Medicine Qatar, Education City, Qatar Foundation , Doha ,","place":["Qatar"]},{"name":"Department of Neurology, Weill Cornell Medicine , New York, NY 10065 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence J","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"The Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, 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