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We compared the accuracy of magnetic resonance imaging (MRI)\u2010derived locus coeruleus integrity, neocortical beta\u2010amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta\u2010amyloid PET\u2010negative.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We included 188 asymptomatic individuals (70.78\u2009\u00b1\u200911.51\u2009years, 58% female) who underwent 3T\u2010MRI of the locus coeruleus, Pittsburgh compound\u2010B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB\u2212 sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR\u2010sum\u2010of\u2010boxes) over a time span of 6\u2009years were evaluated with Cox proportional hazard models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 26 (21%) individuals with high EC FTP in the CDR\u2009=\u20090\/PiB\u2212 sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC]\u2009=\u200985%) compared with PiB (AUC\u2009=\u200977%) or hippocampal volume (AUC\u2009=\u200976%). Based on the Youden\u2010index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut\u2010off, lower locus coeruleus integrity was associated with a two\u2010fold increase in clinical progression, including mild cognitive impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Locus coeruleus integrity has promise as a low\u2010cost, non\u2010invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta\u2010amyloid individuals. ANN NEUROL 2024;96:650\u2013661<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.27022","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T10:58:15Z","timestamp":1721041095000},"page":"650-661","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Lower Locus Coeruleus Integrity Signals Elevated Entorhinal Tau and Clinical Progression in Asymptomatic Older Individuals"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9871-6829","authenticated-orcid":false,"given":"Nina","family":"Engels\u2010Dom\u00ednguez","sequence":"first","affiliation":[{"name":"Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg Maastricht University  Maastricht The Netherlands"},{"name":"The Athinoula A. 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