{"doi":"10.1002/alz.14595","title":"Human herpesvirus‐associated transposable element activation in human aging brains with Alzheimer's disease","abstract":"INTRODUCTION: Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. METHODS: We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies. RESULTS: We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model. DISCUSSION: Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation. HIGHLIGHTS: Via analysis of bulk RNA-seq data in two large-scale human brain biobanks, ROS/MAP (n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB (n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV-positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type-specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long-range enhancer-promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 (NEAT1). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real-world patient database. Using the HEK293 tau P301S model and U2OS mt-Keima cell model, we determined that valacyclovir treatment rescued tau-associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy-level mechanistically supported clinical benefits of valacyclovir in real-world patient data.","journal":"Alzheimer s & Dementia","year":2025,"id":515597,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8717,"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":1379924,"name":"Shuqin Cao","orcid":"0000-0002-1143-8919","position":1,"is_corresponding":false},{"id":1150919,"name":"Yi Shi","orcid":"0000-0003-3575-4948","position":2,"is_corresponding":false},{"id":1150920,"name":"Anna Sun","orcid":"0009-0007-6467-0563","position":3,"is_corresponding":false},{"id":93,"name":"Margaret E. Flanagan","orcid":"0009-0008-7078-3545","position":4,"is_corresponding":false},{"id":108604,"name":"James B. Leverenz","orcid":"0000-0002-0896-0749","position":5,"is_corresponding":false},{"id":247916,"name":"Andrew A. Pieper","orcid":"0000-0001-6299-6577","position":6,"is_corresponding":false},{"id":107313,"name":"Jae U. Jung","orcid":"0000-0003-4559-8774","position":7,"is_corresponding":false},{"id":2716,"name":"Jeffrey L. Cummings","orcid":"0000-0001-8944-4158","position":8,"is_corresponding":false},{"id":347286,"name":"Evandro Fei Fang","orcid":"0000-0003-0355-7202","position":9,"is_corresponding":false},{"id":12547,"name":"Pengyue Zhang","orcid":"0000-0002-7381-9303","position":10,"is_corresponding":false},{"id":69831,"name":"Feixiong Cheng","orcid":"0000-0002-1736-2847","position":11,"is_corresponding":false},{"id":1329701,"name":"Yayan Feng","orcid":"0000-0002-3932-0779","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T02:48:39.436300Z","pmid":"39985481","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":[]}