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Cognitively unimpaired\u2010decliners (CU\u2010D) were based on a linear regression model. In a subsample with MRI (<jats:italic>n<\/jats:italic>\u00a0=\u00a0220), we examined relationships of CU\u2010D with white matter (WM) microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) and cortical volume in brain regions commonly affected in AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CU\u2010D participants had lower FA in the superior longitudinal fasciculus (SLF) (<jats:italic>p<\/jats:italic>\u00a0=\u00a0&lt;\u00a00.001) and higher MD in the SLF (<jats:italic>p<\/jats:italic>\u00a0=\u00a0&lt;\u00a00.001), and cingulum adjacent to the corpus callosum (<jats:italic>p<\/jats:italic>\u00a0=\u00a0&lt;\u00a00.001) and genu (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.006) compared to cognitively unimpaired\u2010stable (CU\u2010S) participants. The groups did not differ in cortical brain volumes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CU\u2010D participants had poorer WM microstructure in brain tracts affected early in AD. Early interventions can target individuals that fit the CU\u2010D criteria.<\/jats:p><\/jats:sec>","DOI":"10.1002\/gps.70060","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:07:48Z","timestamp":1741756068000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain Signatures of Very Early Cognitive Decline in Asymptomatic Middle\u2010Aged Offspring of People With Alzheimer's Disease"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1068-4816","authenticated-orcid":false,"given":"Nadia","family":"Ramsingh","sequence":"first","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung\u2010Mo","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Yale Center for Analytical Sciences Yale University  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxia","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramit","family":"Ravona\u2010Springer","sequence":"additional","affiliation":[{"name":"The Joseph Sagol Neuroscience Center Sheba Medical Center  Tel HaShomer Israel"},{"name":"Faculty of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Department of Psychiatry Sheba Medical Center  Tel HaShomer Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail","family":"Livny","sequence":"additional","affiliation":[{"name":"The Joseph Sagol Neuroscience Center Sheba Medical Center  Tel HaShomer Israel"},{"name":"Faculty of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Division of Diagnostic Imaging Sheba Medical Center  Tel HaShomer Israel"},{"name":"Sagol School of Neuroscience Tel\u00a0Aviv University  Tel\u00a0Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laili","family":"Soleimani","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara B.","family":"Bendlin","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Medicine and Public Health University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adar","family":"Matatov","sequence":"additional","affiliation":[{"name":"The Joseph Sagol Neuroscience Center Sheba Medical Center  Tel HaShomer Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tal","family":"Niv","sequence":"additional","affiliation":[{"name":"The Joseph Sagol Neuroscience Center Sheba Medical Center  Tel HaShomer Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamar","family":"Shamir","sequence":"additional","affiliation":[{"name":"The Joseph Sagol Neuroscience Center Sheba Medical Center  Tel HaShomer Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ithamar","family":"Ganmore","sequence":"additional","affiliation":[{"name":"The Joseph Sagol Neuroscience Center Sheba Medical Center  Tel HaShomer Israel"},{"name":"Faculty of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Memory Clinic and Department of Neurology Sheba Medical Center  Tel HaShomer Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Heymann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Maccabi Health Services  Tel Aviv Israel"},{"name":"Meuhedat Healthcare  Tel Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"James J. 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