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In human autopsy brains, the number of pS65-Ub positive cells increases with age but is also associated with Lewy body (LB), neurofibrillary tangles (NFT), and senile plaque (SP) burden. Through a recent genome-wide association study, we identified two genetic modifiers of pS65-Ub levels,\n                    <jats:italic>APOE4<\/jats:italic>\n                    and\n                    <jats:italic>ZMIZ1<\/jats:italic>\n                    rs6480922. While LB, NFT, and SP pathologies often coexist in Lewy body dementia (LBD), it is unclear how genetic factors and comorbid neuropathologies interact to impact mitophagy in vulnerable brain regions. We therefore measured levels of the age and disease marker pS65-Ub in the hippocampus and amygdala of 371 LBD cases. Significant and independent associations with pS65-Ub levels were observed for each of the three pathologies LB, NFT, and SP in both regions, and the presence of\n                    <jats:italic>APOE4<\/jats:italic>\n                    significantly strengthened the association between NFT and pS65-Ub in the hippocampus. While no interaction between LB and SP pathologies was observed regarding association with pS65-Ub, a significant interaction between LB and NFT pathologies on pS65-Ub accumulation was found in the amygdala, which was primarily observed in carriers of the minor allele of\n                    <jats:italic>ZMIZ1<\/jats:italic>\n                    rs6480922. In summary, our study revealed complex interactions between LB pathology, NFT pathology, and genetic mitophagy modifiers in LBD brains, highlighting potential convergent molecular mechanisms underlying \u03b1-synuclein- and tau-associated mitophagy alterations.\n                  <\/jats:p>","DOI":"10.1007\/s00401-025-02964-6","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T16:19:51Z","timestamp":1764605991000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia"],"prefix":"10.1007","volume":"150","author":[{"given":"Xu","family":"Hou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyrique","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabienne C.","family":"Fiesel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Launia J.","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunsuke","family":"Koga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Owen A.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfdieter","family":"Springer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"2964_CR1","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1016\/S0140-6736(15)00462-6","volume":"386","author":"Z Walker","year":"2015","unstructured":"Walker Z, Possin KL, Boeve BF, Aarsland D (2015) Lewy body dementias. 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