Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease

Background: Alzheimer’s Disease (AD) is the most common neurodegenerative disease and the leading cause of dementiaamong senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation.Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been anumber of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however nogeneral consensus has been reached yet on the correlation between mtDNA haplogroups and AD.Methodology/Principal Findings: We applied for the first time a high resolution analysis (sequencing of displacement loopand restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association betweenmtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from centraland northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor forAD (OR = 1.85, 95% CI:1.04–3.23) in particular for females (OR = 2.19, 95% CI:1.06–4.51) and independently from the APOEgenotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample isconsidered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD inearly studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p = 0.031), and it mightaccount for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAsbelonging to H5 revealed that AD patients showed a trend towards a higher number (p = 0.052) of sporadic mutations intRNA and rRNA genes when compared with controls.Conclusions: Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help inidentifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associatedwith complex traits such as AD.