{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:21:27Z","timestamp":1791814887369,"version":"4.3.4"},"posted":{"date-parts":[[2026,7,13]]},"group-title":"Bioinformatics","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["U19AG032438"],"award-info":[{"award-number":["U19AG032438"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["U19AG024904"],"award-info":[{"award-number":["U19AG024904"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["1-K01-AG090753-01"],"award-info":[{"award-number":["1-K01-AG090753-01"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["SG-20-690363-DIAN"],"award-info":[{"award-number":["SG-20-690363-DIAN"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"award":["KL2TR002346"],"award-info":[{"award-number":["KL2TR002346"]}],"id":[{"id":"https:\/\/ror.org\/04pw6fb54","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Disease progression modeling (DPM) or \u201camyloid time\u201d is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Inter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>DPM is fundamentally constrained by dynamic range, variability, and test\u2013retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>National Institute on Aging, Alzheimer\u2019s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health &amp; Welfare and Ministry of Science and ICT, Spanish Institute of Health.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.08.737258","type":"posted-content","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T19:30:19Z","timestamp":1783971019000},"source":"Crossref","is-referenced-by-count":1,"title":["Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3624-2784","authenticated-orcid":false,"given":"Julie K.","family":"Wisch","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqiao","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Millar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole S.","family":"McKay","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9351-585X","authenticated-orcid":false,"given":"Aleksandra","family":"Beric","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110, USA"},{"name":"NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis (MO), 63108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"},{"name":"NeuroGenomics and Informatics Center, Washington University in Saint Louis School of Medicine, St. Louis, MO 63108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Stauber","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Preminger","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9045-1072","authenticated-orcid":false,"given":"Mathias","family":"Jucker","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), T\u00fcbingen, Germany"},{"name":"Hertie-Institute for Clinical Brain Research, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"name":"Department of Neurology, Washington University School of Medicine, Saint Louis, MO, 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"R. Barth\u00e9lemy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, Saint Louis, MO, 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7792-1698","authenticated-orcid":false,"given":"Jasmeer","family":"Chhatwal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie S","family":"Ryan","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, University College London Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne E.","family":"Schindler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 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":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"},{"name":"NeuroGenomics and Informatics Center, Washington University in Saint Louis School of Medicine, St. Louis, MO 63108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8114-0552","authenticated-orcid":false,"given":"Tammie L.S.","family":"Benzinger","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6854-5547","authenticated-orcid":false,"given":"Celeste M.","family":"Karch","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-1702","authenticated-orcid":false,"given":"Randall J.","family":"Bateman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"McDade","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Llibre-Guerra","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Dominantly Inherited Alzheimer Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Alzheimer Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2109-2955","authenticated-orcid":false,"given":"Brian A.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St. Louis (MO), 63110 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 (MO), 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ibanez","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis (MO), 63110 USA"},{"name":"NeuroGenomics and Informatics Center, Washington University in Saint Louis School of Medicine, St. Louis, MO 63108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071609150646000_2026.07.08.737258v1.1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/978-1-0716-3195-9_17","volume-title":"in Machine Learning for Brain Disorders","volume":"197","year":"2023"},{"key":"2026071609150646000_2026.07.08.737258v1.2","doi-asserted-by":"crossref","unstructured":"Birdsill, A. 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