{"doi":"10.1126/science.adl2992","title":"Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming","abstract":"Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD. Reprogrammed LOAD neurons exhibit Aβ-dependent neurodegeneration, and treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both Aβ deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.","journal":"Science","year":2024,"id":417659,"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":64,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":313059,"name":"Ji‐Sun Kwon","orcid":null,"position":1,"is_corresponding":false},{"id":1203988,"name":"Yudong Ren","orcid":"0000-0003-4777-9325","position":2,"is_corresponding":false},{"id":311627,"name":"Shawei Chen","orcid":"0009-0007-8019-3285","position":3,"is_corresponding":false},{"id":509512,"name":"Courtney K. Walker","orcid":"0000-0002-7826-4044","position":4,"is_corresponding":false},{"id":783691,"name":"Xinguo Lu","orcid":"0000-0001-8452-7608","position":5,"is_corresponding":false},{"id":294996,"name":"K. Lynn Cates","orcid":"0000-0001-7716-153X","position":6,"is_corresponding":false},{"id":642158,"name":"Hande Karahan","orcid":"0000-0003-3192-7362","position":7,"is_corresponding":false},{"id":552525,"name":"Sanja Sviben","orcid":"0000-0001-5918-4834","position":8,"is_corresponding":false},{"id":420916,"name":"James A. J. Fitzpatrick","orcid":"0000-0002-7907-3602","position":9,"is_corresponding":false},{"id":276128,"name":"Clarissa Valdez","orcid":null,"position":10,"is_corresponding":false},{"id":52692,"name":"Henry Houlden","orcid":"0000-0002-2866-7777","position":11,"is_corresponding":false},{"id":301876,"name":"Celeste M. Karch","orcid":"0000-0002-6854-5547","position":12,"is_corresponding":false},{"id":228359,"name":"Randall J. Bateman","orcid":"0000-0002-7729-1702","position":13,"is_corresponding":false},{"id":228358,"name":"Chihiro Sato","orcid":"0000-0002-7639-8727","position":14,"is_corresponding":false},{"id":421667,"name":"Steven Mennerick","orcid":"0000-0003-0868-0664","position":15,"is_corresponding":false},{"id":479138,"name":"Marc I. Diamond","orcid":"0000-0002-8085-7770","position":16,"is_corresponding":false},{"id":307902,"name":"Jungsu Kim","orcid":"0000-0002-6931-8581","position":17,"is_corresponding":false},{"id":226532,"name":"Rudolph E. Tanzi","orcid":"0000-0002-7032-1454","position":18,"is_corresponding":false},{"id":27592,"name":"David M. Holtzman","orcid":"0000-0002-3400-0856","position":19,"is_corresponding":false},{"id":294997,"name":"Andrew S. Yoo","orcid":"0000-0002-0304-3247","position":20,"is_corresponding":false},{"id":353106,"name":"Zhao Sun","orcid":"0000-0003-0763-7963","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":null,"created_at":"2026-07-19T01:56:56.807779Z","pmid":"39088624","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":[]}