Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Rebecca R. Valentino et. al PDBP authors: Bradley Boeve & Kejal Kantarci


Lewy body dementia are comprised of two distinct, but clinically related, disorders—Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) [22, 30]. The timing of dementia onset determines the exact clinical diagnosis, whereby dementia onset before or less than a year after parkinsonism is classified as DLB, and dementia onset more than one year after parkinsonism is classified as PDD [30]. DLB is one of the most common forms of dementia after Alzheimer’s disease (AD), accounting for approximately 23% of all dementia cases [49]. Currently there is no treatment to prevent or cure DLB and disease course is progressive and eventually fatal.


A total of 806 DLB subjects (N=360 clinically diagnosed DLB cases and N=446 autopsy-confirmed Lewy body disease cases that were assessed as having a high likelihood of DLB (LBD-hDLB) – of which N=48 were present in both series) and 910 controls were included in this study. Clinical DLB patients were diagnosed by neurologists at Mayo Clinic in Jacksonville, FL or Rochester, MN and were recruited as part of the Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging. Pathologically confirmed LBD cases were obtained from the brain bank for neurodegenerative disorders at Mayo Clinic in Jacksonville, FL and were evaluated by a single neuropathologist (Dr. Dennis Dickson). LBD cases were all assessed as having a high likelihood of DLB according to the criteria of the fourth report of the DLB consortium [30]. Controls were recruited by Dr. Zbigniew Wszolek and his colleagues from Mayo Clinic in Jacksonville, FL and were absent of neurological disease. All subjects provided written consent prior to study commencement and were Caucasian, non-Hispanic, and unrelated. Age at DLB diagnosis in clinically diagnosed DLB cases, age at death in pathologically confirmed LBD-hDLB cases, and age at blood draw in controls, and sex was collected for all subjects. Additionally, neuropathological measures for Lewy body counts and substantia nigra (SN) neuronal loss were available for 242 (54.3%) LBD-hDLB cases.


Associations of haplogroups with risk of clinical DLB and LBD-hDLB are detailed in Table 2. After adjusting for age and sex, no statistically significant associations were observed after Bonferroni correction (P <0.0024 considered significant). However, a nominally significant (P <0.05) association was reported between sub-haplogroup H and lower risk of clinical DLB (OR=0.61, P=0.006). This association was consistent when additionally adjusting for the number of apolipoprotein E4 (APOE4) alleles (OR=0.59, P = 0.004). No other associations approached statistical significance in any other series (all P ≥ 0.057, Table 2). Interestingly though, despite mitochondrial sub-haplogroup H not being strongly associated with LBD-hDLB (OR=0.87, P = 0.34), the protective association observed in the clinical DLB series was almost nominally significant when examining the combined DLB series (OR=0.78, P = 0.057).


We have conducted a comprehensive study of the role of mitochondrial genomic variation, in the form of mitochondrial haplogroups and sub-haplogroups, in clinical DLB and pathologically confirmed LBD-hDLB. Moreover, this is one of the first studies to explore the association of mtDNA background with neuropathological LB counts and neuronal loss measures in LBD-hDLB brains. Our data suggests that mitochondrial sub-haplogroup H may be protective against clinical DLB risk, independent of APOE4 background, and this may be indirectly influenced by the suggestive association that sub-haplogroup H is protective against neuronal loss in substantia nigra tissue. Additional assessments and replication studies are warranted to further validate and expand on this data.




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