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      Evidence for Sub-Haplogroup H5 of Mitochondrial DNA as a Risk Factor for Late Onset Alzheimer's Disease

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          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.

          Methodology/Principal Findings

          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.


          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.

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          Most cited references 53

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          Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.

          Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
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            Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.

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              A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.

               C. Wallace (2004)
              Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

                Author and article information

                [1 ]Department of Experimental Pathology, University of Bologna, Bologna, Italy
                [2 ]CIG-Interdepartmental Center for Biophysics and Biocomplexity Studies, University of Bologna, Bologna, Italy
                [3 ]Department of Genetics and Microbiology, University of Pavia, Pavia, Italy
                [4 ]Department of Cell and Environmental Biology, University of Perugia, Perugia, Italy
                [5 ]National Council Research, Institute of Neuroscience, Padova, Italy
                [6 ]Institute of Biochemistry, Medical Faculty Charité, Berlin, Germany
                [7 ]Italian National Research Center for Aging (I.N.R.C.A.), Ancona, Italy
                [8 ]Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy
                [9 ]Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
                [10 ]Regional Center for Cerebral Aging, Valdagno, Vicenza, Italy
                [11 ]NeuroBioGen Lab-Memory Clinic, “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy
                [12 ]Proteomics Unit, “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy
                [13 ]Department of Cell Biology, University of Calabria, Rende, Cosenza, Italy
                Mental Health Research Institute of Victoria, Australia
                Author notes

                Conceived and designed the experiments: AS AT CF. Performed the experiments: AS EB CP FR FT. Analyzed the data: AS VB EB PS NM GR GP. Contributed reagents/materials/analysis tools: AS AA EB MM SS FM MC FO BN AMC LB RG CG GB SS GC. Wrote the paper: AS VB GR AT CF.

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                6 August 2010
                : 5
                : 8
                Santoro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Pages: 11
                Research Article
                Genetics and Genomics/Complex Traits
                Neurological Disorders/Alzheimer Disease
                Public Health and Epidemiology/Epidemiology
                Evolutionary Biology/Human Evolution



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