[Roles of mitochondrial dysfunctions in Alzheimer's disease--contribution of deficiency of ALDH 2].

Mitochondrial aldehyde dehydrogenase 2 (ALDH 2) deficiency is caused by a mutant allele in the Mongoloids. To examine whether genetic constitutions affecting aldehyde metabolism influence the risk for late-onset Alzheimer's disease (LOAD), we performed a case-control study in the Japanese population on the deficiency in ALDH 2 caused by the dominant-negative mutant allele of the ALDH 2 gene (ALDH 2 * 2). In a comparison of 447 patients with sex, age and region matched non-demented controls, the genotype frequency carrying the ALDH 2 * 2 allele was significantly higher in the patients than in the controls (p = 0.001, Odds ratio 1.6). Logistic regression analysis indicates that carriage of the ALDH 2 * 2 allele is an independent risk for LOAD of the epsilon 4 allele of the apolipoprotein E gene (APOE-epsilon 4) (p = 0.002). Moreover, the odds ratio for LOAD in carriers of the ALDH 2 * 2 allele was almost twice that in non-carriers irrespective of status with regard to the APOE-epsilon 4 allele. Among patients homozygous for the APOE-epsilon 4 allele, age at onset of LOAD was significantly lower in those with than without the ALDH 2 * 2 allele. In addition, dosage of the ALDH 2 * 2 allele significantly affected age at onset of patients homozygous for the APOE-epsilon 4 allele. These results indicate that the ALDH 2 deficiency is a risk for LOAD, synergistically acting with the APOE-epsilon 4 allele.