Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor f or sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect o f APOE isoforms on neuronal cell oxidative death is known. Because of the r ole of the mitochondrial genome (mtDNA) in oxidative phosphorylation and ox idative stress, an interaction between APOE polymorphism and mtDNA inherite d variability in the genetic susceptibility to sporadic AD can be hypothesi zed. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carrier. We found th at the frequency distribution of mtDNA haplogroups is different between eps ilon4 carriers and non-carriers (P=0.018, thus showing non-random associati on between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged m ore than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogr oups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 a llele, lowering the epsilon4 odds ratio from statistically significant to n on-significant values.