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Candidate genes were examined in a set of dementia cases and controls (<jats:italic>n<\/jats:italic>\u00a0=\u00a03712). Western blotting was conducted of the wild\u2010type and mutant protein of the final candidate.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the <jats:italic>TRIM25<\/jats:italic> gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss\u2010of\u2010function mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A <jats:italic>TRIM25<\/jats:italic> nonsense mutation (p.C168*) is associated with autosomal dominant early\u2010onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>TRIM25 protein studies support that the mutation exerts its effect through loss of function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.12913","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T13:53:51Z","timestamp":1672235631000},"page":"2805-2815","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<i>TRIM25<\/i> mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early\u2010onset autosomal dominant dementia with amyloid load and parkinsonism"],"prefix":"10.1002","volume":"19","author":[{"given":"Estrella","family":"G\u00f3mez\u2010Tortosa","sequence":"first","affiliation":[{"name":"Department of Neurology Fundaci\u00f3n Jim\u00e9nez D\u00edaz  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yalda","family":"Baradaran\u2010Heravi","sequence":"additional","affiliation":[{"name":"Neurodegenerative Brain Diseases VIB Center for Molecular Neurology VIB  Antwerp Belgium"},{"name":"Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lubina","family":"Dillen","sequence":"additional","affiliation":[{"name":"Neurodegenerative Brain Diseases VIB Center for Molecular Neurology VIB  Antwerp Belgium"},{"name":"Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nila Roy","family":"Choudhury","sequence":"additional","affiliation":[{"name":"Infection Medicine University of Edinburgh The Chancellor's Building  Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Ag\u00fcero Rabes","sequence":"additional","affiliation":[{"name":"Department of Neurology Fundaci\u00f3n Jim\u00e9nez D\u00edaz  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juli\u00e1n","family":"P\u00e9rez\u2010P\u00e9rez","sequence":"additional","affiliation":[{"name":"Secugen S.L  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cemile","family":"Kocoglu","sequence":"additional","affiliation":[{"name":"Neurodegenerative Brain Diseases VIB Center for Molecular Neurology VIB  Antwerp Belgium"},{"name":"Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Jos\u00e9","family":"Sainz","sequence":"additional","affiliation":[{"name":"Department of Neurology Fundaci\u00f3n Jim\u00e9nez D\u00edaz  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Ruiz Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Alzheimer's Centre Reina Sof\u00eda\u2010CIEN Foundation\u2010ISCIII  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"T\u00e9llez","sequence":"additional","affiliation":[{"name":"Department of Immunology Fundaci\u00f3n Jim\u00e9nez D\u00edaz  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc\u00eda","family":"Cremades\u2010Jimeno","sequence":"additional","affiliation":[{"name":"Department of Immunology Fundaci\u00f3n Jim\u00e9nez D\u00edaz  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca","family":"C\u00e1rdaba","sequence":"additional","affiliation":[{"name":"Department of 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