{"doi":"10.1002/alz.70198","title":"Genome‐wide association analysis identifies <i>APOE</i> as a mitophagy modifier in Lewy body disease","abstract":"INTRODUCTION: Phosphorylated ubiquitin (p-S65-Ub) is generated during PINK1-PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p-S65-Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear. METHODS: To identify novel mitophagy regulators, we performed a genome-wide association study using p-S65-Ub level as a quantitative trait in 1012 autopsy-confirmed Lewy body disease (LBD) samples. RESULTS: We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4-mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role. DISCUSSION: Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience. HIGHLIGHTS: p-S65-Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p-S65-Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology-dependent and pathology-independent mechanisms. ZMIZ1 was linked to reduced p-S65-Ub and neuropathology indicative of protection.","journal":"Alzheimer s & Dementia","year":2025,"id":518306,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"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":54748,"name":"Michael G. Heckman","orcid":"0000-0003-3770-9331","position":1,"is_corresponding":false},{"id":314473,"name":"Fabienne C. Fiesel","orcid":"0000-0002-1919-9676","position":2,"is_corresponding":false},{"id":238165,"name":"Shunsuke Koga","orcid":"0000-0001-8868-9700","position":3,"is_corresponding":false},{"id":368351,"name":"Alexandra I. Soto‐Beasley","orcid":"0000-0002-0153-1917","position":4,"is_corresponding":false},{"id":314467,"name":"Jens O. Watzlawik","orcid":"0000-0003-0610-0267","position":5,"is_corresponding":false},{"id":230874,"name":"Jing Zhao","orcid":"0000-0002-4520-6307","position":6,"is_corresponding":false},{"id":271282,"name":"Rebecca R. Valentino","orcid":"0000-0001-7253-961X","position":7,"is_corresponding":false},{"id":287564,"name":"Patrick W. Johnson","orcid":"0000-0001-8365-1375","position":8,"is_corresponding":false},{"id":642946,"name":"Launia J. White","orcid":"0000-0003-0251-9431","position":9,"is_corresponding":false},{"id":308845,"name":"Zachary Quicksall","orcid":"0000-0002-8791-0925","position":10,"is_corresponding":false},{"id":308848,"name":"Joseph S. Reddy","orcid":"0000-0002-1783-4453","position":11,"is_corresponding":false},{"id":52693,"name":"José Brás","orcid":"0000-0001-8186-0333","position":12,"is_corresponding":false},{"id":331123,"name":"Rita Guerreiro","orcid":"0000-0001-5879-3486","position":13,"is_corresponding":false},{"id":233772,"name":"Na Zhao","orcid":"0000-0001-8648-9422","position":14,"is_corresponding":false},{"id":230893,"name":"Guojun Bu","orcid":"0000-0003-3491-1016","position":15,"is_corresponding":false},{"id":54753,"name":"Dennis W. Dickson","orcid":"0000-0001-7189-7917","position":16,"is_corresponding":false},{"id":17435,"name":"Owen A. Ross","orcid":"0000-0003-4813-756X","position":17,"is_corresponding":false},{"id":314474,"name":"Wolfdieter Springer","orcid":"0000-0002-1178-3149","position":18,"is_corresponding":false},{"id":314468,"name":"Xu Hou","orcid":"0000-0003-3011-4378","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:49:09.679930Z","pmid":"40309932","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":[]}