{"doi":"10.1002/ana.26043","title":"Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model","abstract":"OBJECTIVE: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. METHODS: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. RESULTS: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. INTERPRETATION: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952-966.","journal":"Annals of Neurology","year":2021,"id":151365,"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":83,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9624,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":643165,"name":"Tien‐Phat V. Huynh","orcid":"0000-0001-8375-7938","position":1,"is_corresponding":false},{"id":643166,"name":"Yang Shi","orcid":"0000-0002-5441-0529","position":2,"is_corresponding":false},{"id":643167,"name":"Rosemary J. Jackson","orcid":"0000-0002-5478-5611","position":3,"is_corresponding":false},{"id":643168,"name":"Mary Beth Finn","orcid":"0000-0003-3980-9221","position":4,"is_corresponding":false},{"id":230678,"name":"Melissa Manis","orcid":"0000-0001-7912-2016","position":5,"is_corresponding":false},{"id":643169,"name":"Caroline Massad Francis","orcid":"0000-0001-9874-5112","position":6,"is_corresponding":false},{"id":643170,"name":"Ainsley C. Tran","orcid":"0000-0001-8627-7390","position":7,"is_corresponding":false},{"id":250210,"name":"Patrick M. Sullivan","orcid":"0000-0001-8402-2634","position":8,"is_corresponding":false},{"id":236544,"name":"Jason D. Ulrich","orcid":"0000-0002-4743-926X","position":9,"is_corresponding":false},{"id":19610,"name":"Bradley T. Hyman","orcid":"0000-0002-7959-9401","position":10,"is_corresponding":false},{"id":416784,"name":"Tracy Cole","orcid":null,"position":11,"is_corresponding":false},{"id":27592,"name":"David M. Holtzman","orcid":"0000-0002-3400-0856","position":12,"is_corresponding":false},{"id":239694,"name":"Alexandra Litvinchuk","orcid":"0000-0002-0591-7948","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:43:11.293086Z","pmid":"33550655","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":[]}