{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:58:49Z","timestamp":1782280729597,"version":"3.54.5"},"posted":{"date-parts":[[2025,11,5]]},"group-title":"Biochemistry","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL122770"],"award-info":[{"award-number":["R01HL122770"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R35HL155008"],"award-info":[{"award-number":["R35HL155008"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK135621"],"award-info":[{"award-number":["R01DK135621"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and the accumulation of amyloid plaques and neurofibrillary tangles. While prior research has focused mainly on protein aggregation and neuroinflammation, emerging evidence suggests that ionic imbalances, particularly involving sodium (Na+) and potassium (K+), may contribute to AD progression. Na+ and K+ are critical for maintaining neuronal membrane potential, regulating action potential firing, and supporting neurotransmitter function. Although studies primarily focused on absolute Na+ concentrations, the Na+\/K+ ratio may provide a more sensitive marker of ionic dysregulation. Given that the Na+\/K+ gradient is actively maintained by the Na\/K-ATPase pump, a target known to be vulnerable in AD, we hypothesized that the Na+\/K+ ratio is altered in AD. We analyzed postmortem tissue from the prefrontal cortex, thalamus, and cerebrospinal fluid (CSF) of 97 human subjects (67 AD, 30 controls). AD cases exhibited a significant increase in the Na+\/K+ ratio in the thalamus and CSF, driven primarily by elevated Na+ levels. The Na+\/K+ ratio positively correlated with Braak tangle stage, suggesting an association with AD progression. These findings provide novel insights into ionic dysregulation in AD and suggest that the CSF Na+\/K+ ratio may serve as a valuable biomarker of disease severity and progression. Future research should explore the potential of targeting ionic homeostasis as a therapeutic strategy in AD.<\/jats:p>","DOI":"10.1101\/2025.11.04.686539","type":"posted-content","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T21:30:21Z","timestamp":1762378221000},"source":"Crossref","is-referenced-by-count":1,"title":["Elevated Na\n                  <sup>+<\/sup>\n                  \/K\n                  <sup>+<\/sup>\n                  Ratio in Alzheimer\u2019s Disease: A Potential Biomarker for Braak Stage"],"prefix":"10.64898","author":[{"given":"Yuma","family":"Mizuno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyue","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick G.","family":"Kehoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Feng Earley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025110710300946000_2025.11.04.686539v1.1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10080479"},{"key":"2025110710300946000_2025.11.04.686539v1.2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"2025110710300946000_2025.11.04.686539v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-008-0296-x"},{"key":"2025110710300946000_2025.11.04.686539v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"2025110710300946000_2025.11.04.686539v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.07.004"},{"key":"2025110710300946000_2025.11.04.686539v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.16257"},{"key":"2025110710300946000_2025.11.04.686539v1.7","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-016-0390-8"},{"key":"2025110710300946000_2025.11.04.686539v1.8","first-page":"17","article-title":"Ionic Imbalances and Coupling in Synchronization of Responses in Neurons","volume":"2","year":"2019","journal-title":"J"},{"key":"2025110710300946000_2025.11.04.686539v1.9","doi-asserted-by":"crossref","unstructured":"McCormick, D.A. CHAPTER 5 - Membrane Potential and Action Potential. In From Molecules to Networks, Byrne, J.H. , Roberts, J.L. , Eds.; Academic Press: Burlington, 2004; pp. 115\u2013140.","DOI":"10.1016\/B978-012148660-0\/50006-8"},{"key":"2025110710300946000_2025.11.04.686539v1.10","doi-asserted-by":"crossref","unstructured":"Clausen, M.J.V. ; Poulsen, H. Sodium\/Potassium Homeostasis in the Cell. In Metallomics and the Cell, Banci, L. , Ed.; Springer Netherlands: Dordrecht, 2013; pp. 41\u201367.","DOI":"10.1007\/978-94-007-5561-1_3"},{"key":"2025110710300946000_2025.11.04.686539v1.11","doi-asserted-by":"crossref","unstructured":"Pohl, H.R. ; Wheeler, J.S. ; Murray, H.E. Sodium and Potassium in Health and Disease. In Interrelations between Essential Metal Ions and Human Diseases, Sigel, A. , Sigel, H. , Sigel, R.K.O. , Eds.; Springer Netherlands: Dordrecht, 2013; pp. 29\u201347.","DOI":"10.1007\/978-94-007-7500-8_2"},{"key":"2025110710300946000_2025.11.04.686539v1.12","doi-asserted-by":"publisher","DOI":"10.3390\/nu8070444"},{"key":"2025110710300946000_2025.11.04.686539v1.13","doi-asserted-by":"publisher","DOI":"10.54660\/IJPGRR.2025.2.2.01-10"},{"key":"2025110710300946000_2025.11.04.686539v1.14","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1951.sp004546"},{"key":"2025110710300946000_2025.11.04.686539v1.15","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006909927287"},{"key":"2025110710300946000_2025.11.04.686539v1.16","doi-asserted-by":"publisher","DOI":"10.3390\/cells11244075"},{"key":"2025110710300946000_2025.11.04.686539v1.17","first-page":"275","article-title":"[Is Na,K-ATPase the target of oxidative stress?]","volume":"121","year":"1996","journal-title":"Biull Eksp Biol Med"},{"key":"2025110710300946000_2025.11.04.686539v1.18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1150171"},{"key":"2025110710300946000_2025.11.04.686539v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.12000"},{"key":"2025110710300946000_2025.11.04.686539v1.20","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.279893"},{"key":"2025110710300946000_2025.11.04.686539v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(87)80400-5"},{"key":"2025110710300946000_2025.11.04.686539v1.22","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae075"},{"key":"2025110710300946000_2025.11.04.686539v1.23","doi-asserted-by":"publisher","DOI":"10.4067\/s0716-97602002000200012"},{"key":"2025110710300946000_2025.11.04.686539v1.24","doi-asserted-by":"publisher","DOI":"10.1159\/000096326"},{"key":"2025110710300946000_2025.11.04.686539v1.25","doi-asserted-by":"publisher","DOI":"10.1007\/s10827-008-0132-4"},{"key":"2025110710300946000_2025.11.04.686539v1.26","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-141869"},{"key":"2025110710300946000_2025.11.04.686539v1.27","doi-asserted-by":"publisher","DOI":"10.3945\/an.114.006783"},{"key":"2025110710300946000_2025.11.04.686539v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-020-00536-7"},{"key":"2025110710300946000_2025.11.04.686539v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/advances\/nmab036"},{"key":"2025110710300946000_2025.11.04.686539v1.30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2109794"},{"key":"2025110710300946000_2025.11.04.686539v1.31","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0127-z"},{"key":"2025110710300946000_2025.11.04.686539v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx320"},{"key":"2025110710300946000_2025.11.04.686539v1.33","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25245789"},{"key":"2025110710300946000_2025.11.04.686539v1.34","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12802"},{"key":"2025110710300946000_2025.11.04.686539v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12962"},{"key":"2025110710300946000_2025.11.04.686539v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1688-z"},{"key":"2025110710300946000_2025.11.04.686539v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamda.2022.10.001"},{"key":"2025110710300946000_2025.11.04.686539v1.38","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-191339"},{"key":"2025110710300946000_2025.11.04.686539v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/s12263-024-00741-w"},{"key":"2025110710300946000_2025.11.04.686539v1.40","doi-asserted-by":"publisher","DOI":"10.1111\/jon.13216"},{"key":"2025110710300946000_2025.11.04.686539v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)03510-X"},{"key":"2025110710300946000_2025.11.04.686539v1.42","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00093.2019"},{"key":"2025110710300946000_2025.11.04.686539v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00654-5"},{"key":"2025110710300946000_2025.11.04.686539v1.44","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00371"},{"key":"2025110710300946000_2025.11.04.686539v1.45","doi-asserted-by":"publisher","DOI":"10.4021\/jocmr2010.02.263w"},{"key":"2025110710300946000_2025.11.04.686539v1.46","doi-asserted-by":"publisher","DOI":"10.3390\/ijms251910807"},{"key":"2025110710300946000_2025.11.04.686539v1.47","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00126.2004"},{"key":"2025110710300946000_2025.11.04.686539v1.48","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.108.125807"},{"key":"2025110710300946000_2025.11.04.686539v1.49","doi-asserted-by":"publisher","DOI":"10.21873\/invivo.12275"},{"key":"2025110710300946000_2025.11.04.686539v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.10.007"},{"key":"2025110710300946000_2025.11.04.686539v1.51","doi-asserted-by":"publisher","DOI":"10.1007\/s00701-009-0354-x"},{"key":"2025110710300946000_2025.11.04.686539v1.52","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01185-x"},{"key":"2025110710300946000_2025.11.04.686539v1.53","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002923"},{"key":"2025110710300946000_2025.11.04.686539v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"2025110710300946000_2025.11.04.686539v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102936"},{"key":"2025110710300946000_2025.11.04.686539v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/srep27738"},{"key":"2025110710300946000_2025.11.04.686539v1.57","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421182112"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.04.686539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:05:25Z","timestamp":1782277525000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.04.686539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":57,"URL":"https:\/\/doi.org\/10.1101\/2025.11.04.686539","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.3390\/ijms27031247","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,11,5]]},"subtype":"preprint"}}