{"doi":"10.1126/sciadv.aba5933","title":"Dedifferentiation and neuronal repression define familial Alzheimer’s disease","abstract":"Identifying the systems-level mechanisms that lead to Alzheimer's disease, an unmet need, is an essential step toward the development of therapeutics. In this work, we report that the key disease-causative mechanisms, including dedifferentiation and repression of neuronal identity, are triggered by changes in chromatin topology. Here, we generated human induced pluripotent stem cell (hiPSC)-derived neurons from donor patients with early-onset familial Alzheimer's disease (EOFAD) and used a multiomics approach to mechanistically characterize the modulation of disease-associated gene regulatory programs. We demonstrate that EOFAD neurons dedifferentiate to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis reveals that transcriptional alterations in the cellular state are orchestrated by changes in histone methylation and chromatin topology. Furthermore, we demonstrate that these mechanisms are observed in EOFAD-patient brains, validating our hiPSC-derived neuron models. The mechanistic endotypes of Alzheimer's disease uncovered here offer key insights for therapeutic interventions.","journal":"Science Advances","year":2020,"id":110292,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":525202,"name":"Qing Liu","orcid":"0000-0003-2712-6028","position":1,"is_corresponding":false},{"id":313922,"name":"Gary P. Schroth","orcid":"0000-0002-3055-056X","position":2,"is_corresponding":false},{"id":108599,"name":"Douglas Galasko","orcid":"0000-0001-6195-3241","position":3,"is_corresponding":false},{"id":459244,"name":"Shauna H. Yuan","orcid":"0000-0003-4058-4146","position":4,"is_corresponding":false},{"id":260530,"name":"Steven L. Wagner","orcid":"0000-0003-4674-9474","position":5,"is_corresponding":false},{"id":108044,"name":"Shankar Subramaniam","orcid":"0000-0002-8059-4659","position":6,"is_corresponding":false},{"id":525201,"name":"Andrew B. Caldwell","orcid":"0000-0002-2850-7677","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":null,"created_at":"2026-07-18T23:12:57.988348Z","pmid":"33188013","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":[]}