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A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-\u03b2 and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised <jats:italic>n<\/jats:italic>\u2009=\u2009196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, <jats:sup>11<\/jats:sup>C-Pittsburgh compound-B-PET, <jats:sup>18<\/jats:sup>F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for <jats:italic>n<\/jats:italic>\u2009=\u2009186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for <jats:italic>n<\/jats:italic>\u2009=\u2009163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-\u03b2, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-\u03b2, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-\u03b2, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-\u03b2 and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-\u03b2, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.<\/jats:p>","DOI":"10.1038\/s41380-021-01290-z","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T11:09:58Z","timestamp":1632913798000},"page":"7813-7822","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Association of cortical microstructure with amyloid-\u03b2 and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6639-8141","authenticated-orcid":false,"given":"Elena","family":"Rodriguez-Vieitez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5714-9282","authenticated-orcid":false,"given":"Victor","family":"Montal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4199-2304","authenticated-orcid":false,"given":"Jorge","family":"Sepulcre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Lois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Hanseeuw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Vilaplana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P.","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Properzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Amariglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn V.","family":"Papp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gad A.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fortea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa A.","family":"Sperling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-1059","authenticated-orcid":false,"given":"Patrizia","family":"Vannini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"1290_CR1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1212\/WNL.42.3.631","volume":"42","author":"PV Arriagada","year":"1992","unstructured":"Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. 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BH reported grants from the Belgian National Fund for Scientific Research and the Belgian Foundation for Alzheimer Research during the conduct of the study, and personal fees paid to his institution from Roche, Biogen and GE Healthcare outside the submitted work. APS has served on medical advisory boards for Janssen Pharmaceuticals and Biogen. KVP has served as an advisor to Biogen Idec and Digital Cognition Technologies. GAM has received research salary support from Eisai Inc., Eli Lilly, Janssen Alzheimer Immunotherapy, Novartis, and Genentech, and consulting fees from Grifols Shared Services North America, Inc., Eisai Inc., and Pfizer. JF has served as a consultant for Novartis and Lundbeck, has received honoraria for lectures from Roche, NovoNordisk, Esteve and Biogen, and has served at advisory boards for AC Immune, Zambon and Lundbeck. KAJ and RAS are involved in public\u2013private partnership clinical trials sponsored by the NIH and Eli Lilly and Co., who owns the distribution rights to Flortaucipir (AV-1451), but they do not have any personal financial relationship with Eli Lilly. All other authors report no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}