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This study developed models to forecast trajectories and improve trial efficiency.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n Models were trained on longitudinal Preclinical Alzheimer's Cognitive Composite (PACC) data up to 240 weeks from the Phase III A4 study of solanezumab. Baseline inputs included demographics, apolipoprotein E (\n APOE<\/jats:italic>\n ) \u03b54, clinical scores, amyloid positron emission tomography (PET), plasma pTau217, magnetic resonance imaging (MRI), and tau PET (sub\u2010study). Stochastic gradient boosting was used, with evaluation via cross\u2010validation and trial simulations.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n The best model without tau PET used pTau217, clinical, and MRI data (\n R<\/jats:italic>\n 2<\/jats:sup>\n \u00a0=\u00a00.32; area under the receiver operating characteristic curve (AUROC) for classifying a 0.5\u2010point PACC decline\u00a0=\u00a078.6%). Replacing MRI with tau PET improved performance (\n R<\/jats:italic>\n 2<\/jats:sup>\n \u00a0=\u00a00.42; AUROC\u00a0=\u00a083.1%). Predicted trajectories as a prognostic covariate reduced sample sizes by 35% and increased power from 80% to 94.7%.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n Prognostic models can predict decline in preclinical AD and improve trial efficiency.<\/jats:p>\n <\/jats:sec>\n \n CLINICALTRIALS.GOV IDENTIFIERS<\/jats:title>\n NCT02008357 (Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4))<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n Models forecast 4.5\u2010year cognitive decline in amyloid\u2010positive preclinical Alzheimer's disease (AD).<\/jats:p>\n <\/jats:list-item>\n \n Plasma pTau217 and tau positron emission tomography (PET) standardized uptake value ratios (SUVRs) in early\u2010accumulating regions are key predictors.<\/jats:p>\n <\/jats:list-item>\n \n Tau PET improves prediction beyond plasma, magnetic resonance imaging (MRI), and clinical measures.<\/jats:p>\n <\/jats:list-item>\n \n Forecasted decline as a prognostic covariate improves power and cuts sample size in trial simulations.<\/jats:p>\n <\/jats:list-item>\n \n Alternative models underperform yet retain practical utility when tau PET or pTau217 is unavailable.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70702","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T10:17:37Z","timestamp":1758709057000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Multimodal prognostic modeling of individual cognitive trajectories to enhance trial efficiency in preclinical Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2059-9252","authenticated-orcid":false,"given":"Viswanath","family":"Devanarayan","sequence":"first","affiliation":[{"name":"Clinical Research Eisai Inc Nutley New Jersey USA"},{"name":"Department of Mathematics, Statistics, and Computer Science University of Illinois Chicago Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Donohue","sequence":"additional","affiliation":[{"name":"Alzheimer's Therapeutic Research Institute Keck School of Medicine University of Southern California San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa A.","family":"Sperling","sequence":"additional","affiliation":[{"name":"Center for Alzheimer's Research and Treatment Department of Neurology Brigham and Women's Hospital Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Departments of Radiology and Neurology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanqing","family":"Ye","sequence":"additional","affiliation":[{"name":"Clinical Research Eisai Inc Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Charil","sequence":"additional","affiliation":[{"name":"Clinical Research Eisai Inc Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Doherty","sequence":"additional","affiliation":[{"name":"Clinical Research Eisai Ltd. Hatfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science Stanford University School of Medicine Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rema","family":"Raman","sequence":"additional","affiliation":[{"name":"Alzheimer's Therapeutic Research Institute Keck School of Medicine University of Southern California San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Aisen","sequence":"additional","affiliation":[{"name":"Alzheimer's Therapeutic Research Institute Keck School of Medicine University of Southern California San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn D.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Clinical Research Eisai Inc Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Irizarry","sequence":"additional","affiliation":[{"name":"Clinical Research Eisai Inc Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shobha","family":"Dhadda","sequence":"additional","affiliation":[{"name":"Clinical Research Eisai Inc Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.6669"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000431"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170448"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.09.002"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-018-0455-y"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-022-01185-z"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012022"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.12.003"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008081"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14073"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14411"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.12134"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.1424"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2016.08.017"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.5272"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01348-z"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12621"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2018.06.007"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2017.03.006"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12363"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2024.122"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40708-019-0099-0"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae043"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00880-x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35712-5"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12032"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13565"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.202100349"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1515\/ijb-2021-0072"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.8054"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70045"},{"key":"e_1_2_8_35_1","unstructured":"U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Oncology Center of Excellence (OCE).Adjusting for covariates in randomized clinical Trials for Drugs and Biological Products Guidance for Industry. 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