{"doi":"10.1002/alz.70729","title":"TREM2‐apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants","abstract":"INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2-apoE3 interactions and effects of AD-associated variants on TREM2-apoE3 interactions are not fully understood. METHODS: We used consensus protein-protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2-apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects. RESULTS: Our experimentally consistent TREM2-apoE3 complex structure identified new potential TREM2-apoE3 interactions alongside the known interactions. TREM2-apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4 variants altered TREM2-apoE binding mode and conformational stability. DISCUSSION: This study determined an experimentally consistent TREM2-apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2-apoE3 binding mode. Understanding TREM2-apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants. HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD). An experimentally consistent TREM2-apoE3 complex structure was determined. New potential interaction interfaces between TREM2 and apoE3 were identified. TREM2-apoE3 interactions altered TREM2 and apoE3 conformation. AD-associated TREM2 R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2-apoE complexes.","journal":"Alzheimer s & Dementia","year":2025,"id":527173,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9637,"is_data_producer":false,"deposit_databanks":null,"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":1212235,"name":"Ryan A. Tuckey","orcid":"0000-0003-2096-7924","position":1,"is_corresponding":false},{"id":556247,"name":"Hunter B. Dean","orcid":"0000-0002-6202-4337","position":2,"is_corresponding":false},{"id":374652,"name":"Tom J. Brett","orcid":"0000-0002-6871-6676","position":3,"is_corresponding":false},{"id":246148,"name":"Erik D. Roberson","orcid":"0000-0002-1810-9763","position":4,"is_corresponding":false},{"id":556249,"name":"Yuhua Song","orcid":"0000-0002-2583-850X","position":5,"is_corresponding":false},{"id":1120924,"name":"Rory A. Greer","orcid":"0000-0002-4582-4228","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41085188","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":[]}