{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T21:49:07Z","timestamp":1782510547487,"version":"3.54.5"},"posted":{"date-parts":[[2026,5,22]]},"group-title":"Neurology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"abstract":"<jats:p>Late-onset unexplained epilepsy is a potential harbinger of dementia, likely driven by network hyperexcitability that facilitates amyloid-\u03b2 release and tau propagation. Dampening this activity with antiseizure medications offers a potential disease modifying strategy, yet whether specific agents differentially alter this neurodegenerative trajectory remains unknown. Here, we emulated a target trial using global real-world federated data on patients with late-onset unexplained epilepsy to compare dementia risk across antiseizure monotherapies. Using data from over 75 million adults aged 55 years or older, we found that sodium channel blockers were associated with a 27% lower hazard of incident all-cause dementia (hazard ratio = 0.73, 95% confidence interval 0.61- 0.88) and 34% lower hazard of Alzheimer's disease (hazard ratio = 0.66, 0.49 -0.88), compared with levetiracetam\/brivaracetam. While the class effect was protective, individual agents such as phenytoin, carbamazepine, and lamotrigine showed divergent safety and efficacy profiles. We replicated these findings in both a Down syndrome cohort and the external National Alzheimer's Coordinating Center dataset. Our results suggest that targeting neuronal excitability with sodium channel blockers is associated with lower risk of dementia, prioritizing the repurposing of these agents for dementia prevention trials.<\/jats:p>","DOI":"10.64898\/2026.05.20.26353714","type":"posted-content","created":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T17:19:58Z","timestamp":1779643198000},"source":"Crossref","is-referenced-by-count":1,"title":["Sodium channel blockers are associated with reduced dementia risk in late-onset unexplained epilepsy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-7163","authenticated-orcid":false,"given":"Carolina","family":"Ferreira-Atuesta","sequence":"first","affiliation":[{"name":"University Hospital of Zurich;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1438-7544","authenticated-orcid":false,"given":"Kai Michael","family":"Schubert","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9238-6622","authenticated-orcid":false,"given":"Xin You","family":"Tai","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford; Oxford, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1308-6048","authenticated-orcid":false,"given":"Daniela","family":"Noain","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1657-2110","authenticated-orcid":false,"given":"Daria","family":"Skwarzynska","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2037-3424","authenticated-orcid":false,"given":"Matthias T.","family":"Wyss","sequence":"additional","affiliation":[{"name":"Neuroscience Center Zurich, University and ETH Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-6066","authenticated-orcid":false,"given":"Simon J.","family":"Schreiner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-9934","authenticated-orcid":false,"given":"Hans H.","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5677-2214","authenticated-orcid":false,"given":"Trey","family":"Hedden","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai; New York, NY, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9445-4545","authenticated-orcid":false,"given":"Johan","family":"Zelano","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg; Gothenburg, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6861-8806","authenticated-orcid":false,"given":"Tony","family":"Marson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool; Liverpool, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-1626","authenticated-orcid":false,"given":"Gregory Y. H.","family":"Lip","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital; Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9588-2944","authenticated-orcid":false,"given":"Gashirai K.","family":"Mbizvo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool; Liverpool, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-071X","authenticated-orcid":false,"given":"Marian","family":"Galovic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich; Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.20.26353714","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T17:19:58Z","timestamp":1779643198000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.05.20.26353714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.05.20.26353714","relation":{},"subject":[],"published":{"date-parts":[[2026,5,22]]},"subtype":"preprint"}}