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While morphometric measures from T1\u2010weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Our study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age\u2010related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>These findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Free water fraction has higher sensitivity to normal brain aging.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Free water fraction has stronger associations with early AD and regional tau deposition.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/dad2.12627","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T06:59:46Z","timestamp":1722236386000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["NODDI in gray matter is a sensitive marker of aging and early AD changes"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1024-4653","authenticated-orcid":false,"given":"Xi","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Przybelski","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research Division of Biomedical Statistics and Informatics Mayo 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