Abstract: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in ethanol metabolism. It is involved in acetaldehyde detoxification. A polymorphism of the ALDH2 gene is specific to North-East Asians. Sensitivity to ethanol is highly associated with this polymorphism (ALDH2*2 allele), which is responsible for a deficiency of ALDH2 activity. We first show that this deficiency influences the risk for late-onset Alzheimer's disease (LOAD) by a case-control study in a Japanese population. In a comparison of 447 patients with sex, age, and region-matched non-demented controls, the genotype frequency for the ALDH2*2 allele was significantly higher in the patients than in the controls (P=0.001). Next, we examined the combined effect of the ALDH2*2 and the apolipoprotein E4 allele (APOE-ε4), which has been confirmed to be a risk factor for LOAD. The ALDH2*2 allele more significantly affected frequency and age at onset in patients with APOE-ε4 than in those without it. These results indicate that the ALDH2 deficiency is a risk factor for LOAD, acting synergistically with the APOE-ε allele. Next, to elucidate the molecular mechanism involved, we obtained ALDH2-deficient cell lines by introducing mouse mutant ALDH2 cDNA into PC12 cells. We speculate that ALDH2 may act to oxidize toxic aldehyde derivatives. Then, we found that the ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated from peroxidized fatty acids. In addition, the ALDH2-deficient transfectants were sensitive to oxidative insult induced by antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2-nonenal. Mitochondrial ALDH2 functions as a protector against oxidative stress.