{"doi":"10.1172/jci169131","title":"APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading","abstract":"Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD.","journal":"Journal of Clinical Investigation","year":2023,"id":319232,"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":57,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1027940,"name":"Aishwarya Nambiar","orcid":"0000-0002-4206-5027","position":1,"is_corresponding":false},{"id":233379,"name":"Michael R. Strickland","orcid":"0000-0002-3899-5651","position":2,"is_corresponding":false},{"id":848309,"name":"Choonghee Lee","orcid":"0000-0001-8907-5858","position":3,"is_corresponding":false},{"id":622885,"name":"Samira Parhizkar","orcid":"0000-0001-5807-190X","position":4,"is_corresponding":false},{"id":1027941,"name":"A Moore","orcid":"0000-0002-7259-5619","position":5,"is_corresponding":false},{"id":242342,"name":"Erik S. Musiek","orcid":"0000-0002-8873-0360","position":6,"is_corresponding":false},{"id":236544,"name":"Jason D. Ulrich","orcid":"0000-0002-4743-926X","position":7,"is_corresponding":false},{"id":27592,"name":"David M. Holtzman","orcid":"0000-0002-3400-0856","position":8,"is_corresponding":false},{"id":362348,"name":"Chanung Wang","orcid":"0000-0002-6418-3809","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:07:12.004111Z","pmid":"37279069","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":[]}