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Aldehyde dehydrogenase 2 (ALDH2) is an enzyme found in the mitochondrial matrix that plays a central role in alcohol and aldehyde metabolism. A common ALDH2 polymorphism in East Asians descent (called ALDH2*2 or E504K missense variant, SNP ID: rs671), present in approximately 8% of the world’s population, has been associated with a variety of diseases. Recent meta-analyses support the relationship between this ALDH2 polymorphism and Alzheimer’s disease (AD). And AD-like pathology observed in ALDH2–/– null mice and ALDH2*2 overexpressing transgenic mice indicate that ALDH2 deficiency plays an important role in the pathogenesis of AD. Recently, the worldwide increase in alcohol consumption has drawn attention to the relationship between heavy alcohol consumption and AD. Of potential clinical significance, chronic administration of alcohol in ALDH2*2/*2 knock-in mice exacerbates the pathogenesis of AD-like symptoms. Therefore, ALDH2 polymorphism and alcohol consumption likely play an important role in the onset and progression of AD. Here, we review the data on the relationship between ALDH2 polymorphism, alcohol, and AD, and summarize what is currently known about the role of the common ALDH2 inactivating mutation, ALDH2*2, and alcohol in the onset and progression of AD.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that reduces cell injuries via detoxification of lipid-peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal). It is generated exogenously via deep-frying of linoleic acid-rich cooking oils and/or endogenously via oxidation of fatty acids involved in biomembranes. Although its toxicity for human health is widely accepted, the underlying mechanism long remained unknown. In 1998, Yamashima et al. have formulated the “calpain–cathepsin hypothesis” as a molecular mechanism of ischemic neuronal death. Subsequently, they found that calpain cleaves Hsp70.1 which became vulnerable after the hydroxynonenal-induced carbonylation at the key site Arg469. Since it is the pivotal aberration that induces lysosomal membrane rupture, they suggested that neuronal death in Alzheimer’s disease similarly occurs by chronic ischemia via the calpain–cathepsin cascade triggered by hydroxynonenal. For nearly three decades, amyloid β (Aβ) peptide was thought to be a root substance of Alzheimer’s disease. However, because of both the insignificant correlations between Aβ depositions and occurrence of neuronal death or dementia, and the negative results of anti-Aβ medicines tested so far in the patients with Alzheimer’s disease, the strength of the “amyloid cascade hypothesis” has been weakened. Recent works have suggested that hydroxynonenal is a mediator of programmed cell death not only in the brain, but also in the liver, pancreas, heart, etc. Increment of hydroxynonenal was considered an early event in the development of Alzheimer’s disease. This review aims at suggesting ways out of the tunnel, focusing on the implication of hydroxynonenal in this disease. Herein, the mechanism of Alzheimer neuronal death is discussed by focusing on Hsp70.1 with a dual function as chaperone protein and lysosomal stabilizer. We suggest that Aβ is not a culprit of Alzheimer’s disease, but merely a byproduct of autophagy/lysosomal failure resulting from hydroxynonenal-induced Hsp70.1 disorder. Enhancing ALDH2 activity to detoxify hydroxynonenal emerges as a promising strategy for preventing and treating Alzheimer’s disease.