Zeitschriftenartikel

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

Abstract

Allele e 4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer’s disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction be-tween APOE polymorphism and mtDNA inherited vari-ability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyz-ing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE e 4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplo-groups is different between e 4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between e 4 allele and mtDNA hap-logroups. Therefore, the APOE/mtDNA interaction is re-stricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE e 4 allele, lowering the e 4 odds ratio from statistically significant to non-significant values. (SPRINGER-VERLAG)