Aurelia Santoro 1 , 2 , * , Valentina Balbi 1 , Elisa Balducci 1 , Chiara Pirazzini 1 , Francesca Rosini 1 , Francesca Tavano 1 , Alessandro Achilli 3 , 4 , Paola Siviero 5 , Nadia Minicuci 5 , Elena Bellavista 1 , 2 , Michele Mishto 1 , 2 , 6 , Stefano Salvioli 1 , 2 , Francesca Marchegiani 7 , Maurizio Cardelli 7 , Fabiola Olivieri 7 , 8 , Benedetta Nacmias 9 , Andrea Maria Chiamenti 10 , Luisa Benussi 11 , Roberta Ghidoni 11 , 12 , Giuseppina Rose 13 , Carlo Gabelli 10 , Giuliano Binetti 11 , Sandro Sorbi 9 , Gaetano Crepaldi 5 , Giuseppe Passarino 13 , Antonio Torroni 3 , Claudio Franceschi 1 , 2
6 August 2010
Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among 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 a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.
We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (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 APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNA Gln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p = 0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p = 0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.