mtDNA inherited and somatic variability in Alzheimer's Disease

Sporadic Alzheimer's Disease (AD), the late onset form of AD, is a complex disease in which several susceptibility genes interact with each other and with environmental factors, in modulating the risk to develop AD. Oxidative stress and mitochondria are hypothesized to play a major role in AD onset and progression. We investigated the role of mitochondrial DNA (mtDNA) in AD, evaluating mitochondrial inherited variability (haplogroups) and its possible interaction with APOE, a nuclear gene well known as risk factor for AD, as well as mitochondrial somatic variability (accumulation of mutations). We investigated the association of mtDNA haplogroups with AD in a case–control study on 237 AD patients and 237 age–matched controls from the Veneto region. Male AD patients with haplogroups U and K appear to protect (O.R.: 0,403; 95% CI: 0,167–0,970; p= 0,043), while those with haplogroups H and V appear to have an increased AD risk (O.R.: 1,953; 95% CI: 1,013–3,767; p=0,046). In female patients no correlation between mtDNA haplogroups and disease was found. In both groups (male and female AD patients) no correlation between mtDNA haplogroups and APOE gene variants was found. Moreover, the accumulation of sporadic mutations was analyzed by resequencing the entire mtDNA molecule (16.569 bp) in two brain areas (hippocampus and cerebellum) from 10 AD patients and in the hippocampus of 9 age–matched non AD affected controls. The analysis of the mtDNA sequences showed a significant prevalence of heteroplasmic mutations in the hippocampus from AD patients in comparison with cerebellum (a brain area much less affected by AD specific lesions) from the same subjects and with hippocampus of non demented controls. Moreover, all the mutations (even the homoplasmic ones) found in hippocampus of AD patients were mainly present in mtDNA genes codifying for complex I and IV subunits of the respiratory chain, that are known to be more damaged in AD. Finally the T146C (previously described) and the A1871G (not known in literature) mutations have been found only in some AD patients but not in controls, suggesting a possible AD specificity.