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This study applied hierarchical clustering and machine learning\u2013based feature selection to identify biomarkers associated with disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Cross\u2010sectional blood\u2010based biomarkers were analyzed from 211 DS participants (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a079 cognitively stable [CS];\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a072 mild cognitive impairment [MCI];\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a060 AD dementia [DS\u2010AD]). These included markers of amyloid, tau, neurodegeneration, and inflammation. Clustering grouped biomarkers. Decision trees classified disease stage, and Shapley values identified the strongest predictors of disease stage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>The strongest predictors overall were neurofilament light chain (NfL), tau\/amyloid beta (A\u03b2)40, A\u03b242\/A\u03b240, alpha\u20102\u2010macroglobulin (A2M), and interleukin (IL)\u201010. Within the CS group, NfL, tau\/A\u03b240, A2M, and IL\u201010 were strong predictors. In MCI, A\u03b242\/A\u03b240, NfL, A2M, and IL\u201010 were strong predictors. In DS\u2010AD, A\u03b242\/A\u03b240, NfL, and tau\/A\u03b240 were the top predictors. Cluster membership varied based on disease stage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings reveal evolving biomarker signatures and clustering patterns across cognitive stages, underscoring their potential for disease monitoring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/dad2.70325","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T08:55:26Z","timestamp":1775465726000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Application of machine learning to blood\u2010based biomarkers of Alzheimer's disease in Down syndrome"],"prefix":"10.1002","volume":"18","author":[{"given":"Patrick H.","family":"Luckett","sequence":"first","affiliation":[{"name":"Division of Neurotechnology Department of Neurological Surgery Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Family Medicine Institute for Translational Research University of North Texas Health Science Center  Fort Worth Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sid","family":"O'Bryant","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Neuroscience Institute for Translational Research University of North Texas Health Science Center  Fort Worth Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Mapstone","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Irvine  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad T.","family":"Christian","sequence":"additional","affiliation":[{"name":"Waisman Center University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Handen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Head","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Laboratory Medicine, and Neurology School of Medicine University of California Irvine  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beau M.","family":"Ances","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer's Biomarker Consortium\u2010Down 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