{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:06:26Z","timestamp":1789560386087,"version":"build-2803163510"},"reference-count":67,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:00:00Z","timestamp":1748044800000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG064614"],"award-info":[{"award-number":["R01AG064614"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG078964"],"award-info":[{"award-number":["R01AG078964"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG058501"],"award-info":[{"award-number":["RF1AG058501"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp; Dementia"],"published-print":{"date-parts":[[2025,5]]},"abstract":"Abstract<\/jats:title>\n \n INTRODUCTION<\/jats:title>\n This study investigated the role of the ubiquitin\u2013proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.<\/jats:p>\n <\/jats:sec>\n \n METHOD<\/jats:title>\n The SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n Subtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS\u2010activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late\u2010stage tau biomarkers, microglia, and axonal degeneration.<\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n The rise in UPS proteins alongside tau\u2010related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n This study investigates the ubiquitin\u2010proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression.<\/jats:p>\n <\/jats:list-item>\n \n Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset.<\/jats:p>\n <\/jats:list-item>\n \n Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD.<\/jats:p>\n <\/jats:list-item>\n \n Dynamic UPS changes align with A\/T biological staging: UPS proteins were shown to increase across A\u03b2\/tau (A\/T) groups, with largest increases in the A+\/T+ group, reinforcing their role in late\u2010stage tau pathology and disease progression.<\/jats:p>\n <\/jats:list-item>\n \n These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau\u2010pathology\u2010driven neurodegeneration.<\/jats:p>\n <\/jats:list-item>\n \n This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70243","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T05:00:28Z","timestamp":1748062828000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Ubiquitin\u2013proteasome system in the different stages of dominantly inherited Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Haiyan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology Washington University in St. Louis St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quoc","family":"Bui","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Washington University in St. Louis St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Hassenstab","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University in St. Louis St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Radiology Washington University in St. Louis St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie L. 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