{"doi":"10.1002/alz.70702","title":"Multimodal prognostic modeling of individual cognitive trajectories to enhance trial efficiency in preclinical Alzheimer's disease","abstract":"INTRODUCTION: Cognitive decline in asymptomatic preclinical Alzheimer's disease (AD) is slow and variable, limiting detection of treatment effects. This study developed models to forecast trajectories and improve trial efficiency. METHODS: 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 (APOE) ε4, clinical scores, amyloid positron emission tomography (PET), plasma pTau217, magnetic resonance imaging (MRI), and tau PET (sub-study). Stochastic gradient boosting was used, with evaluation via cross-validation and trial simulations. RESULTS: = 0.42; AUROC = 83.1%). Predicted trajectories as a prognostic covariate reduced sample sizes by 35% and increased power from 80% to 94.7%. DISCUSSION: Prognostic models can predict decline in preclinical AD and improve trial efficiency. GOV IDENTIFIERS: NCT02008357 (Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4)) HIGHLIGHTS: Models forecast 4.5-year cognitive decline in amyloid-positive preclinical Alzheimer's disease (AD). Plasma pTau217 and tau positron emission tomography (PET) standardized uptake value ratios (SUVRs) in early-accumulating regions are key predictors. Tau PET improves prediction beyond plasma, magnetic resonance imaging (MRI), and clinical measures. Forecasted decline as a prognostic covariate improves power and cuts sample size in trial simulations. Alternative models underperform yet retain practical utility when tau PET or pTau217 is unavailable.","journal":"Alzheimer s & Dementia","year":2025,"id":520140,"datarank":0.5384344137775137,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.24654789141921668,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.24654789141921668,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9246,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02008357"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":51716,"name":"Michael Donohue","orcid":"0000-0001-6026-2238","position":1,"is_corresponding":false},{"id":55000,"name":"Reisa A. Sperling","orcid":"0000-0003-1535-6133","position":2,"is_corresponding":false},{"id":1229162,"name":"Keith A. Johnson","orcid":"0000-0002-4685-5173","position":3,"is_corresponding":false},{"id":416713,"name":"Yuanqing Ye","orcid":"0000-0001-5708-8961","position":4,"is_corresponding":false},{"id":1044402,"name":"Arnaud Charil","orcid":"0000-0002-3437-1710","position":5,"is_corresponding":false},{"id":8624,"name":"T. Doherty","orcid":"0000-0002-4183-5595","position":6,"is_corresponding":false},{"id":51246,"name":"Lü Tian","orcid":"0000-0002-5893-0169","position":7,"is_corresponding":false},{"id":226625,"name":"Rema Raman","orcid":"0000-0002-4096-6390","position":8,"is_corresponding":false},{"id":229340,"name":"Paul Aisen","orcid":null,"position":9,"is_corresponding":false},{"id":842885,"name":"Lynn D. Kramer","orcid":null,"position":10,"is_corresponding":false},{"id":67390,"name":"Michael C. Irizarry","orcid":null,"position":11,"is_corresponding":false},{"id":67374,"name":"Shobha Dhadda","orcid":null,"position":12,"is_corresponding":false},{"id":36366,"name":"Viswanath Devanarayan","orcid":"0000-0003-2059-9252","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:49:23.618703Z","pmid":"40990131","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}