Alzheimer's disease is causally associated with mitochondrial dysfunction

Mitochondria regulate energy and metabolic homeostasis, with increasing evidence implicating mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis. Each mitochondrion contains multiple copies of the mitochondrial genome (mtDNA), with mtDNA copy number (mtDNAcn) been used as a surrogate measure of mitochondrial function. Here we evaluate the association of mtDNAcn with neuropathological diagnosis of AD and evaluate shared genetic etiology between AD and mtDNAcn.We evaluated the association of mtDNAcn with a neuropathological diagnosis of AD in 1194 non-Hispanic white subjects (cases = 706, controls = 468) from three cohorts (ROSMAP, MSBB, Mayo) from the Accelerating Medicines Partnership Alzheimer's disease (AMP-AD). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA using whole genome sequencing data from DNA isolated from brain tissue. Neuropathological AD was determined based on neuropathological burden of amyloid plaques and tangles. Logistic regression adjusting for mitochondrial haplogroup, age of death, sex, APOE, post-mortem interval and source tissue was used to evaluate the association of mtDNAcn with AD in each cohort separately and jointly in an inverse weighted fixed-effects meta-analysis (IVW FE). Additionally, we estimated the genetic correlation between mtDNAcn and AD, evaluated the association of a mtDNAcn polygenic risk score (PRS) with clinical AD (cases = 13312, controls = 13119), and conducted bidirectional two-sample Mendelian randomization to estimate the causal relationship between mtDNAcn and AD.Higher mtDNAcn was associated with a reduced risk of neuropathological AD (IVW FE: OR[95%CI] = 0.70 [0.58, 0.84]. mtDNAcn was not genetically correlated with AD (rg = 0.13 (0.16), p = 0.4) and a mtDNAcn PRS was not associated with clinical AD (OR[95%CI] = 1 [0.97, 1.03], p = 0.884). Mendelian randomization did not support a causal relationship between mtDNAcn and AD (OR[95%CI] = 0.93 [0.74, 1.14], p = 0.46).Elevated mtDNAcn estimated from brain tissue was associated with a reduced risk of neuropathological AD, suggesting that mitochondrial dysfunction is associated with AD pathogenesis. However, genetically predicted mtDNAcn estimated from peripheral blood was not associated with AD using genetically informed approaches. As such, further research is needed to determine if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis.