{"doi":"10.1002/alz.70460","title":"Synthetic control methods for n‐of‐1 and parallel‐group trials in Alzheimer's disease: A proof‐of‐concept study using the I‐CONECT","abstract":"INTRODUCTION: With the advent of Alzheimer's disease (AD)-modifying and symptomatic treatments of demonstrated efficacy, enrolling participants as concurrent placebo controls in trials can become increasingly difficult. Synthetic controls have been proposed as a viable alternative to concurrent control groups, but their feasibility and reliability remain untested in AD studies. METHODS: I-CONECT trial, which evaluates conversational interactions on cognition, was used to test synthetic control methods. Data from the National Alzheimer's Coordinating Center-Uniform Data Set was used to create synthetic-controls for I-CONECT participants using two methods: 1) case mapping and 2) case modeling. Efficacy estimates were compared between original versus synthetic-controlled trials. RESULTS: In parallel-group designs, treatment effect sizes for the primary outcome were closely aligned between the original trial (β = 1.67) and synthetic control analyses (β = 1.40-1.65). For n-of-1 designs, the two methods showed high agreement in identifying treatment responders (Kappa = 0.75-0.82). DISCUSSION: Synthetic control methods are feasible and reliable to create alternative controls in AD studies. CLINICAL TRIAL REGISTRATION: NCT02871921. HIGHLIGHTS: Synthetic control methods are feasible and suitable for evaluating treatment effects in various trial designs such as n-of-1, single-arm, and parallel groups. Synthetic control methods can help replicate early-phase Alzheimer's trials, informing go/no-go decisions for larger-scale studies. The choice of similarity algorithms is critical as it affects the quality of historical case mapping. The National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) provided an ideal pool for identifying historical cases with similar demographic, biological, and social characteristics to participants in trials, enabling the creation of synthetic control groups for Alzheimer's clinical research.","journal":"Alzheimer s & Dementia","year":2025,"id":526198,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":3,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02871921"]},"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":490814,"name":"Liu Chen","orcid":"0009-0003-8350-6145","position":1,"is_corresponding":false},{"id":689026,"name":"John R. Dickson","orcid":"0000-0003-0135-7928","position":2,"is_corresponding":false},{"id":447518,"name":"Bo Zhang","orcid":"0000-0003-1574-198X","position":3,"is_corresponding":false},{"id":282975,"name":"Steven E. Arnold","orcid":"0000-0002-9487-415X","position":4,"is_corresponding":false},{"id":325840,"name":"Hiroko H. Dodge","orcid":"0000-0001-7290-8307","position":5,"is_corresponding":false},{"id":533046,"name":"Chao‐Yi Wu","orcid":"0000-0002-2187-6509","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:50:30.402772Z","pmid":"40621876","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":[]}