ALDH2 in stroke: from genetic susceptibility to therapeutic target: a narrative review

Stroke, a devastating neurological disorder resulting from acute cerebrovascular injury, represents the second most common cause of global mortality and a predominant contributor to long-term disability. Aldehyde dehydrogenase 2 (ALDH2) is a critical mitochondrial enzyme that plays a pivotal role in the metabolism of toxic reactive aldehydes, including 4-hydroxynonenal and acetaldehyde. The rs671 (Glu504Lys) polymorphism of ALDH2, which exhibits remarkably high prevalence in East Asian populations, has emerged as a genetic determinant of stroke susceptibility and recovery. This comprehensive review synthesizes contemporary evidence on the multifaceted relationship between ALDH2 genetic variants and stroke. Specifically, we evaluated the association among ALDH2 polymorphisms, stroke incidence, and clinical outcomes. We then delineated the neuroprotective mechanisms mediated by ALDH2 enzymatic activity. Finally, we characterized its dual utility in Mendelian randomization studies, serving as both a robust instrumental variable for alcohol-related research and a direct mediator of cerebrovascular risk with therapeutic potential. By integrating epidemiological findings with mechanistic insights, this review provides a translational perspective on ALDH2 as a biomarker and modifiable target in stroke prevention and management.