Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population

The activity of cytochrome oxidase (CO), the terminal enzyme of the mitocho ndrial electron transport chain, has been reported to be lower in the brain s of Alzheimer disease (AD) patients. This suggests that a modification of mitochondrial DNA (mtDNA) may be responsible for this decrease of CO activi ty. Many mtDNA variants were found by different studies at a higher frequen cy in AD patients, suggesting that mtDNA variants could confer a genetic su sceptibility to AD. In this study, we sequenced the entire mitochondrial ge nome region that encompasses the three CO genes and the 22 mitochondrial tR NA in 69 AD patients and 83 age-matched controls. We detected a total of 95 mtDNA variants, The allele frequencies of the majority of these variants w ere similar in patients and controls, However, a haplotype composed of thre e different modifications (positions: 5633, 7476, and 15812) was present in three of the 69 late-onset AD patients (4.3%) and also in 1 of 16 early-on set AD patients (6.2%) but not in control individuals. Given that one of th ese variants (15812) has already been shown to be associated with another n eurodegenerative disease and that all three modifications are relatively co nserved and their frequencies in the general population is only 0.1%, our d ata suggest that the presence of this haplotype may represent a risk factor for AD. We also found a significant association (P < 0.05) of two other va riants at positions 709 (rRNA 12S) and 15928 (tRNA(Thr)). These two mtDNA v ariants are three times more frequent in control individuals compared with AD patients, suggesting that they may be protective against AD. Am. J, Med, Genet 85: 20-30, 1999. (C) 1999 Wiley-Liss, Inc.