Mitochondrial genome abundance is associated with Alzheimer’s disease neuropathological burden and cognitive function

Abstract

AbstractBackgroundMitochondrial DNA copy number (mtDNAcn) is a measure of mitochondrial genome abundance that is associated with age related diseases. mtDNA can also carry mutations that affect all copies of the mtDNA or only a fraction of the mtDNA molecules (heteroplasmy, mtHz) within an individual cell. To evaluate the role of mitochondrial dysfunction in Alzheimer’s disease (AD) we investigated the association of mtDNAcn levels and mtHz burden with AD neuropathological change and cognitive function.MethodsNeuropathology and genomic data were obtained from 1,381 non‐Hispanic white postmortem brain tissue samples from the Accelerating Medicines Partnership for Alzheimer’s disease (AMP‐AD). neuropathological AD was based on burden of amyloid plaques (CERAD) and neurofibrillary tangles (Braak). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA, and mtHz burden was defined as the number of mtHz variants. The association of mtDNAcn and mtHz with ADNC was evaluated using logistic regression, and amyloid and tau burden using ordinal logistic regression, adjusting for mitochondrial haplogroup, age at death, sex, APOE, post‐mortem interval, study, and tissue. The association of mtDNAcn and mtHz with cognitive performance was evaluated using linear regression (n=785). As mtDNAcn levels estimated from bulk tissue can be influenced by cell type proportion, we conducted a sensitivity analysis adjusting for neuronal cell type proportion estimated from RNAseq (n=494).ResultsHigher mtDNAcn was associated with reduced risk of neuropathological AD and tau burden, but not with amyloid burden, and with higher cognitive performance for perceptual speed, episodic memory, working memory, global cognition, and semantic memory. In sensitivity analyses adjusting for neuronal cell type proportion, mtDNAcn remained significantly associated with neuropathological AD, perceptual speed, and working memory. mtHz was not significantly associated with neuropathology or cognition.ConclusionIncreased mtDNAcn levels estimated from postmortem brain tissue are associated with reduced risk of AD neuropathology and higher cognitive performance. This suggests that mitochondrial genome abundance is associated with AD pathogenesis, potentially by impairing mitochondrial bioenergetics and thereby impacting neuronal or microglia cell function. Drugs that upregulate total mitochondrial genome abundance or boost mitochondrial mass may ameliorate AD pathogenesis.