Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures
Abstract
Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. 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 APOE ε4 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 14, 2022
- Source ID
- 10.1186/s40478-022-01399-4
Entities
People
- Alexandra I. Soto-beasley
- Bradley F. Boeve
- Chloe Ramnarine
- Clifford Jack
- Dennis W. Dickson
- Hugo Botha
- Jonathan Graff-Radford
- Joseph E. Parisi
- Julie A. Fields
- Kejal Kantarci
- Koji Kasanuki
- Melissa E. Murray
- Michael G. Heckman
- Neill R. Graff-radford
- Nilüfer Ertekin-taner
- Owen A. Ross
- Patrick W. Johnson
- R. Ross Reichard
- Rebecca R Valentino
- Rodolfo Savica
- Ronald C. Petersen
- Ronald L. Walton
- Ryan J. Uitti
- Shunsuke Koga
- Tanis J. Ferman
- Val J. Lowe
- Vijay K. Ramanan
- Zbigniew K Wszolek
Organizations
- Alzheimer's Drug Discovery Foundation
- Alzheimer’s Disease Research Center, University of Washington
- Boston Scientific
- Chan Zuckerberg Initiative
- CurePSP
- Florida Department of State
- Foundation for the National Institutes of Health
- GHR Foundation
- Little Family Foundation
- Mayo Clinic
- National Heart, Lung, and Blood Institute
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- National Institute on Deafness and Other Communication Disorders
- Patient-Centered Outcomes Research Institute
- Rainwater Charitable Foundation
- The Michael J. Fox Foundation
- Turner Foundation
- United States Department of Defense