biostudies-literatureHou XNational Institute of Neurological Disorders and StrokeMangurian Foundation Lewy Body Dementia Program at Mayo ClinicTed Turner and FamilyMayo Clinic Office of Research Equity, Inclusion, and DiversityThe Little Family FoundationCongressionally Directed Medical Research ProgramsNIA NIH HHSMayo Clinic Robert and Arlene Kogod Center on AgingFlorida Department of Health-Ed, Ethel Moore Alzheimer's Disease Research ProgramAlzheimer&apos;s AssociationAmerican Parkinson Disease Association Center for Advanced Research at Mayo Clinic JacksonvilleNational Institute on AgingAmerican Brain FoundationNINDS NIH HHSThe Michael J. Fox Foundation for Parkinson's ResearchAlzheimer's AssociationThe Ted Nash Long Life FoundationMayo Clinic Center for Biomedical Discoverye70198https://www.ebi.ac.uk/biostudies/studies/S-EPMC12044520biostudies-literatureUnknown21(4)<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 induceAlzheimer's & dementia : the journal of the Alzheimer's AssociationGenome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.PMC12044520R01 NS078086U19 AG071754U54 NS110435R01 NS110085P30 AG062677R01 AG056366U54NS11043522A07P30AG062677R56 AG062556U54 NS100693U01NS100620U54NS10069322A05RF1 AG046205U01 NS100620U19 AG069701R01AG087165R56AG062556U19AG071754RF1 NS085070R01AG056366P50 NS072187R01 AG089380AARF‐22‐973152AARF-22-973152R01AG089380R01NS110085U19AG069701R01 AG087165RF1NS085070P50NS072187RF1AG046205W81XWH-17-1-0249W81XWH‐17‐1‐0249W81XWH‐17‐1‐0248R01NS078086W81XWH-17-1-0248Fiesel FCDickson DWHeckman MGBu GRoss OAGuerreiro RHou XReddy JSZhao NValentino RRSoto-Beasley AISpringer WKoga SBras JWhite LJJohnson PWQuicksall ZSZhao JWatzlawik JOfalseGenome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 induce2025-01-01T00:00:00Z2025 Apr2026-06-02T06:40:27.079Z2025-07-08T03:12:54.734ZS-EPMC120445204030993210.1002/alz.70198