ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.Acta neuropathologica · 2026Article
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia.Acta neuropathologica · 2025Article
- APOE4 promotes nigral tau hyperphosphorylation through cholesterol in atherosclerosis.Cell death discovery · 2025Article
- Article
- Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain-muscle-liver axis to slow down aging and neurodegeneration: a narrative review.European journal of medical research · 2025Review
- Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Genetic susceptibility and environmental factors in dementia with Lewy bodies: Converging pathogenic mechanisms.Frontiers in neurologyReview
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Authors and funding
19 authors.
Funding
Abstract
introductionPhosphorylated 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.
methodsTo 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.
resultsWe 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.
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