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Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of <jats:italic>APOE<\/jats:italic> \u03b54 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.<\/jats:p>","DOI":"10.1186\/s40478-022-01399-4","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T11:03:04Z","timestamp":1657796584000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures"],"prefix":"10.1186","volume":"10","author":[{"given":"Rebecca R.","family":"Valentino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Ramnarine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick W.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra I.","family":"Soto-Beasley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald L.","family":"Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Koga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kasanuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Uitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Fields","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Botha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K.","family":"Ramanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejal","family":"Kantarci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val J.","family":"Lowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford R.","family":"Jack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilufer","family":"Ertekin-Taner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Savica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Graff-Radford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C.","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E.","family":"Parisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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Murray personally receives consulting fees from VID Radiopharmaceuticals and has received reimbursements for Mild Cognitive Impairment and NIH study section. MEM is also Co-chair of Digital Pathology working group, Chair\/Immediate Past Chair of Atypical Alzheimer's disease Professional Interest Area group and is on the organizing committee of the Southeastern Neurodegeneration Conference. Julie A. Fields is on the Oversight and Monitoring Board for the SWAN-Aging study that is funded by the NIA but receives no compensation. Hugo Botha received free AAN registration for the Geschwind Award. Vijay K. Ramanan consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, and AVID Radiopharmaceuticals. Kejal Kantarci consults Biogen Inc, and receives research support from Avid Radiopharmaceuticals and Eli Lilly, and funding from NIH and Alzheimer\u2019s Drug Discovery Foundation. Val J. Lowe receives research support from AVID Radiopharmaceuticals and Siemens Healthcare and is a consultant for AVID Radiopharmaceuticals, Eisai, Inc., Bayer Schering Pharma, and Merck Research. Clifford R. Jack is on the Roche advisory board but receives no payments. CRJ is also on the writing committee for the NIA AA research framework. Jonathan Graff-Radford has received payment from American Academy of Neurology for lecturing. Nilufer Ertekin-Taner received payments as a conference speaker for 11th ISABS and the Department of Electrical and Computer Engineering and Computer Science, University of Urbana-Champaigne, and additionally for being a visiting professor at the Department of Neurology, Indiana University School of Medicine, Bloomington, Indiana, as well as at National Center for Geriatrics and Gerontology Nagoya, Japan. NET is a Framingham Heat Study Executive Board member and NIH\/NIA TREAT-AD external advisory Board member. Jonathan Graff-Radford received a payment from American Academy of Neurology for presenting a lecture. Ronald C. Petersen receives royalties from Oxford University Press in UpToDate and consulting fees from Roche, Merck, Biogen, Genentech, and Eisai. RCP is also on the Genentech DSMB advisory board. R. Ross Reichard is the President of American Association of Neuropathologists. Neill R. Graff-Radford receives research support from multicenter studies with Biogen, Abbvie, Lilly, and Novartis, and receives personal royalties for a chapter on NPH in UpToDate. Bradley F. Boeve has served as an investigator for clinical trials sponsored by Biogen, Alector, and EIP Pharma, and serves on the Scientific Advisory Board of the Tau Consortium. Zbigniew K. Wszolek serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301) and Neuraly, Inc. (NLY01-PD-1), and serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. All other authors declare that they have no competing interests to report.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"103"}}