Late-onset Alzheimer´s disease is associated with mitochondrial DNA 7028C/haplogroup H and

Abstract

Mitochondrial dysfunction has been linked to the development of late-oset Alzheimer´s disease (LOAD). Reactive oxygen species (ROS) and mitocohondrial oxidative damage (mtOD) could play a central role in the pathogenesis of LOAD. Recent findings that implicated the amyloid-beta peptide and the common LOAD-risk APOE-ε4 allele in mitochondrial dysfunction contributed to support the Alzheimer´s disease cascade hypothesis. MtDNA mutations have been found in brain tissue from LOAD patients. In addition, common germline mtDNA polymorphisms have been linked to the risk of developing LOAD in the general population. We sought to determine the role of mtDNA single nucleotide polymorphisms (SNPs) that define the common European haplogroups on LOAD-risk. For this purpose, we characterized seven SNPs in a total of 500 patients and 500 healthy controls. Haplogroup H, defined by allele 7028C, was significantly associated with LOAD, with a synergistic effect between 7028C and the APOE-ε4 allele (p<0.0001¸OR=5.30, 95%CI=3.72-7.54). We found a higher rate of heteroplasmy (mtDNA instability, peripheral blood cells) at the D310 polyC tract, that was significantly linked to D310 >7C alleles. The common D310 7C allele was linked to homoplasmy, and the 7028 T + D310 7C haplogroup was significantly protective in our population (p<0.001, OR=0.51, 95%CI=0.36-0.70). Haplogroup H has been associated with a decreased activity of mitochondrial espiratory complex IV and mtOD. This effect could be partly explained by a higher frequency of D310 >7C and instability among 7028 C mtDNA molecules, and could also explain its association with LOAD.