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In this cross\u2010sectional observational study, we investigated the microstructural integrity of the LC\u2013EC pathway in relation to amyloid, tau, and neurodegeneration (ATN) biomarkers along the cognitive spectrum from normal cognition to dementia.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>One hundred twenty\u2010four participants underwent clinical assessment, diffusion\u2010weighted imaging, structural magnetic resonance imaging (N), amyloid (A), and tau (T) positron emission tomography. Diffusivity indices were assessed in the LC\u2013EC tract using a probabilistic atlas, and linear models were used to assess associations with ATN markers and cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Differences in LC\u2013EC microstructural parameters were observed in participants with Braak stage\u00a0&gt;\u00a0I versus Braak 0 (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.020), N+ versus N\u2212 (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001), and cognitively impaired versus unimpaired (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.019). LC\u2013EC mean diffusivity was associated with Mini\u2010Mental State Examination score even after accounting for ATN markers (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.015).<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Our results suggest that LC\u2013EC diffusivity provides complementary information over ATN biomarkers in explaining cognitive impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Locus coeruleus\u2013entorhinal cortex (LC\u2013EC) tract microstructure is associated with tau and especially neurodegeneration markers.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LC\u2013EC tract microstructure is more sensitive to tau pathology and neurodegeneration than tracts commonly affected in Alzheimer's disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LC\u2013EC diffusivity measures provide complementary information over amyloid, tau, and neurodegeneration (ATN) biomarkers.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70126","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:14:01Z","timestamp":1745817241000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Microstructural assessment of the locus coeruleus\u2013entorhinal cortex pathway and association with ATN markers in cognitive impairment"],"prefix":"10.1002","volume":"21","author":[{"given":"Marco","family":"Aiello","sequence":"first","affiliation":[{"name":"IRCCS SYNLAB SDN  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moira","family":"Marizzoni","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Unit IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli  Brescia 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