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As understanding of the underlying causes of AD evolves, numerous animal models have been generated to study the disease. However, persistent therapeutic failures raise questions about the reasons for these shortcomings, including whether they stem from poor target selection and\/or limitations in replicating key aspects of AD pathophysiology in animal models. In this study, a machine learning\u2010based workflow previously reported in the literature was modified and used to identify shared dysregulation in phenotype\u2010defining pathways across both animal models and human datasets\u2014termed translatable pathways. This approach provided a framework for assessing the translational relevance of three widely used AD models: APP\/PS1, 3\u00d7Tg, and 5\u00d7FAD, from hippocampal microarray data. The analysis suggested no translatable pathways in the APP\/PS1 and 3\u00d7Tg preclinical models, whereas key pathways were identified in the 5\u00d7FAD (SREBP control of lipid synthesis and cytotoxic T\u2010lymphocyte pathways) model. Additionally, applying the workflow to publicly available microarray data from ibuprofen\u2010treated mice accurately predicted the clinical failure of ibuprofen for treating AD in human trials. This study highlights the importance of evaluating the translatability of animal models to human disease and provides a suitable framework for improving the selection of preclinical models in Alzheimer's research.<\/jats:p>","DOI":"10.1111\/cts.70387","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T09:33:59Z","timestamp":1762853639000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Translatability of Animal Models for Alzheimer's Disease Using a Machine Learning Based Workflow"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0708-8434","authenticated-orcid":false,"given":"Alex","family":"Foster\u2010Powell","sequence":"first","affiliation":[{"name":"CAPKR, University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2631-3705","authenticated-orcid":false,"given":"Guy","family":"Meno\u2010Tetang","sequence":"additional","affiliation":[{"name":"Neurocrine Biosciences  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-844X","authenticated-orcid":false,"given":"Amin","family":"Rostami\u2010Hodjegan","sequence":"additional","affiliation":[{"name":"CAPKR, University of Manchester  Manchester UK"},{"name":"Certara  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2446-6895","authenticated-orcid":false,"given":"Kayode","family":"Ogungbenro","sequence":"additional","affiliation":[{"name":"CAPKR, University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4848-0440","authenticated-orcid":false,"given":"Donald E.","family":"Mager","sequence":"additional","affiliation":[{"name":"Division of Pharmacokinetics\u2010Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences University at Buffalo, SUNY  Buffalo New York USA"},{"name":"Enhanced Pharmacodynamics, LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/CON.0000000000000313"},{"key":"e_1_2_9_3_1","first-page":"327","volume-title":"2021 Alzheimer's Disease Facts and Figures","author":"Alzheimer's Association","year":"2021"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12450"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/D41586\u2010023\u201000030\u20103"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"e_1_2_9_8_1","unstructured":"\u201cWhat Is Early Onset Familial Alzheimer Disease (eFAD)?\u201d | ALZFORUM."},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742\u20102094\u20101\u201024"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12312"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.90633"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2011.06.009"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/etc.5600"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/intbio\/zyab016"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aay3258"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.727784"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540\u2010024\u201000487\u20106"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103406"},{"key":"e_1_2_9_19_1","first-page":"6","volume-title":"Curation of Over 10\u2009000 Transcriptomic Studies to Enable Data Reuse","author":"Lim N.","year":"2021"},{"key":"e_1_2_9_20_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2010"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11336\u2010021\u201009773\u20102"},{"key":"e_1_2_9_23_1","first-page":"954","volume-title":"A New Family of Power Transformations to Improve Normality or Symmetry","author":"Yeo I. 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