{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:16:50Z","timestamp":1789042610412,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Radiology and Imaging","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K01AG083230"],"award-info":[{"award-number":["K01AG083230"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["RF1AG087271"],"award-info":[{"award-number":["RF1AG087271"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Alzheimer\u2019s disease (AD) is characterized by substantial clinical and biological heterogeneity, with diverse neuroanatomical, cognitive, clinical, functional, and genetic risk profiles that are poorly captured by current diagnostic frameworks. Identifying reproducible disease dimensions is critical for understanding divergent pathophysiological mechanisms and designing future stratified therapeutic interventions. Herein, we applied a semi-supervised machine learning clustering framework and robust reproducibility validation strategies to structural MRI data from 1,757 participants, comprising 1,108 cognitively normal controls (CN) and 649 patients with mild cognitive impairment (MCI) or dementia due to AD. We identified two MRI-based neuroanatomical dimensions of AD: Dimension 1 (\n                  <jats:italic>n<\/jats:italic>\n                  = 393; prevalence \u223c 61%) and Dimension 2 (\n                  <jats:italic>n<\/jats:italic>\n                  = 256; prevalence \u223c 39%). Dimension 1 exhibited widespread cortical and subcortical atrophy, including involvement of the hippocampus, amygdala, parahippocampal, temporal, frontal, and occipital regions, while Dimension 2 showed relatively preserved brain patterns. The two dimensions were not statistically different in demographic characteristics, including age, sex, race, and education (all p &gt; 0.05). Compared to Dimension 2, Dimension 1 had more severe cognitive and clinical impairment, greater functional impairment, elevated\n                  <jats:italic>APOE \u03b54<\/jats:italic>\n                  carrier burden, and higher polygenic risk for AD (p &lt; 0.05). Analysis of individual-level summary neuroanatomical signature expression scores, quantifying each subject\u2019s continuous position along two disease dimensions, revealed that Dimension 1 signature expression correlated strongly with cognitive impairment, clinical severity, functional impairment, and genetic risk, while Dimensional 2 signature expression showed relatively weaker associations. These results reveal that AD encompasses at least two biologically distinct dimensions identifiable from structural MRI profiles and their distinct associations with cognitive, clinical, functional, and genetic profiles. These findings may aid in AD patient stratification for designing targeted therapeutic approaches in the future.\n                <\/jats:p>","DOI":"10.64898\/2026.09.02.26361668","type":"posted-content","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T07:00:12Z","timestamp":1788850812000},"source":"Crossref","is-referenced-by-count":0,"title":["Machine learning-derived Alzheimer\u2019s disease dimensions: neuroanatomical, cognitive, clinical, functional, and genetic risk heterogeneity signatures"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2556-7612","authenticated-orcid":false,"given":"Hoang Nam","family":"Le","sequence":"first","affiliation":[{"name":"Neuroimaging Informatics and Artificial Intelligence (NeuroAI) Laboratory, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Ishrat","sequence":"additional","affiliation":[{"name":"Neuroimaging Informatics and Artificial Intelligence (NeuroAI) Laboratory, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahram","family":"Yaghooti","sequence":"additional","affiliation":[{"name":"Neuroimaging Informatics and Artificial Intelligence (NeuroAI) Laboratory, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taslim","family":"Murad","sequence":"additional","affiliation":[{"name":"Neuroimaging Informatics and Artificial Intelligence (NeuroAI) Laboratory, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram","family":"Sapkota","sequence":"additional","affiliation":[{"name":"Neuroimaging Informatics and Artificial Intelligence (NeuroAI) Laboratory, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa S.","family":"Thakuri","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, School of Medicine, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean F.","family":"Wong","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, Radiology, Psychiatry and Neurology, Kahlert Institute for Addiction Medicine, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh B.","family":"Chand","sequence":"additional","affiliation":[{"name":"Neuroimaging Informatics and Artificial Intelligence (NeuroAI) Laboratory, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Roy and Diana Vagelos Division of Biology & Biomedical Sciences \u2013 Neurosciences; Biomedical Informatics and Data Science; Computational and Systems Biology; Biochemistry, Biophysics, and Structural Biology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091004550983000_2026.09.02.26361668v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(21)00249-8"},{"key":"2026091004550983000_2026.09.02.26361668v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.71345"},{"key":"2026091004550983000_2026.09.02.26361668v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70251"},{"key":"2026091004550983000_2026.09.02.26361668v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14063"},{"key":"2026091004550983000_2026.09.02.26361668v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70156-9"},{"key":"2026091004550983000_2026.09.02.26361668v1.6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001003"},{"key":"2026091004550983000_2026.09.02.26361668v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/S13311-022-01185-Z"},{"key":"2026091004550983000_2026.09.02.26361668v1.8","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0325-5"},{"key":"2026091004550983000_2026.09.02.26361668v1.9","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt47"},{"key":"2026091004550983000_2026.09.02.26361668v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ibneur.2024.02.007"},{"key":"2026091004550983000_2026.09.02.26361668v1.11","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00612-7"},{"key":"2026091004550983000_2026.09.02.26361668v1.12","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-021-01030-9"},{"key":"2026091004550983000_2026.09.02.26361668v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww319"},{"key":"2026091004550983000_2026.09.02.26361668v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05892-0"},{"key":"2026091004550983000_2026.09.02.26361668v1.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1611073113"},{"key":"2026091004550983000_2026.09.02.26361668v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01309-6"},{"key":"2026091004550983000_2026.09.02.26361668v1.17","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007967"},{"key":"2026091004550983000_2026.09.02.26361668v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.02.041"},{"key":"2026091004550983000_2026.09.02.26361668v1.19","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa025"},{"key":"2026091004550983000_2026.09.02.26361668v1.20","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.21070686"},{"key":"2026091004550983000_2026.09.02.26361668v1.21","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2023.0409"},{"key":"2026091004550983000_2026.09.02.26361668v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02069-0"},{"key":"2026091004550983000_2026.09.02.26361668v1.23","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2018.2467"},{"key":"2026091004550983000_2026.09.02.26361668v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2015.12.023"},{"key":"2026091004550983000_2026.09.02.26361668v1.25","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181cb3e25"},{"key":"2026091004550983000_2026.09.02.26361668v1.26","doi-asserted-by":"publisher","DOI":"10.1101\/2025.07.09.25331194"},{"key":"2026091004550983000_2026.09.02.26361668v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.11.073"},{"key":"2026091004550983000_2026.09.02.26361668v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.117248"},{"key":"2026091004550983000_2026.09.02.26361668v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.11.024"},{"key":"2026091004550983000_2026.09.02.26361668v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116450"},{"key":"2026091004550983000_2026.09.02.26361668v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3956(75)90026-6"},{"key":"2026091004550983000_2026.09.02.26361668v1.32","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.8.1091"},{"key":"2026091004550983000_2026.09.02.26361668v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/37.3.323"},{"key":"2026091004550983000_2026.09.02.26361668v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.08.013"},{"key":"2026091004550983000_2026.09.02.26361668v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"2026091004550983000_2026.09.02.26361668v1.36","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbad040"},{"key":"2026091004550983000_2026.09.02.26361668v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0686-2"},{"key":"2026091004550983000_2026.09.02.26361668v1.38","doi-asserted-by":"crossref","unstructured":"Seabold S , Perktold J. statsmodels: Econometric and statistical modeling with python. In: Proceedings of the 9th Python in Science Conference. 2010.","DOI":"10.25080\/Majora-92bf1922-011"},{"key":"2026091004550983000_2026.09.02.26361668v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.patcog.2011.04.006"},{"key":"2026091004550983000_2026.09.02.26361668v1.40","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009058"},{"key":"2026091004550983000_2026.09.02.26361668v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30440-3"},{"key":"2026091004550983000_2026.09.02.26361668v1.42","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000208013"},{"key":"2026091004550983000_2026.09.02.26361668v1.43","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-200868"},{"key":"2026091004550983000_2026.09.02.26361668v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-00435-y"},{"key":"2026091004550983000_2026.09.02.26361668v1.45","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70014"},{"key":"2026091004550983000_2026.09.02.26361668v1.46","doi-asserted-by":"publisher","DOI":"10.3390\/neurolint18020037"},{"key":"2026091004550983000_2026.09.02.26361668v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01878-z"},{"key":"2026091004550983000_2026.09.02.26361668v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01104-7"},{"key":"2026091004550983000_2026.09.02.26361668v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32202-6"},{"key":"2026091004550983000_2026.09.02.26361668v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0228-7"},{"key":"2026091004550983000_2026.09.02.26361668v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.056"},{"key":"2026091004550983000_2026.09.02.26361668v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2015.07.001"},{"key":"2026091004550983000_2026.09.02.26361668v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0032-9"},{"key":"2026091004550983000_2026.09.02.26361668v1.54","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13844"},{"key":"2026091004550983000_2026.09.02.26361668v1.55","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-230740"},{"key":"2026091004550983000_2026.09.02.26361668v1.56","doi-asserted-by":"publisher","DOI":"10.1159\/000527444"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.02.26361668","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:55:25Z","timestamp":1789041325000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.02.26361668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":56,"URL":"https:\/\/doi.org\/10.64898\/2026.09.02.26361668","relation":{},"subject":[],"published":{"date-parts":[[2026,9,7]]},"subtype":"preprint"}}