Abstract
BackgroundAlzheimer'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.Methodology/Principal FindingsWe 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 tRNAGln 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.ConclusionsOur results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.
Highlights
Alzheimer’s Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects
Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD
In our total sample of 1712 Italian subjects (936 AD patients and 776 controls) there is a higher proportion of female (72.9%) and APOE4+ (43.5%) subjects among AD patients relative to controls (60.6% and 13.1%, respectively)
Summary
Alzheimer’s Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. Sporadic AD (SAD) has a complex aetiology due to environmental and genetic factors which taken alone are not sufficient to cause the disease. It has been proposed that SAD can be caused by defects in mitochondrial oxidative phosphorylation (OXPHOS) [3]. Defects in OXPHOS inhibit ATP production, and increase mitochondrial ROS production, which, in turn, can damage the mitochondrial genome (mtDNA). This hypothesis on AD pathogenesis claims that mitochondrial impairment may result from accumulated mtDNA damage that accompanies normal aging, amplified by disease-specific factors [9,3]. 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, no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD
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