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

Abstract

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 narrative review provides an overview of the multifaceted relationship between ALDH2 genetic variants and stroke. We summarize the reported associations of ALDH2 polymorphisms with stroke incidence and clinical outcomes, describe the neuroprotective mechanisms mediated by ALDH2 enzymatic activity, and discuss the dual role of ALDH2 in Mendelian randomization studies-as an instrumental variable in alcohol-related research and as a mediator of cerebrovascular risk with potential therapeutic relevance. Throughout, we emphasize the areas of uncertainty and the conflicting findings that remain in this field. By integrating epidemiological findings with mechanistic insights, this review offers a translational perspective on ALDH2 as a potential biomarker and a candidate target for stroke prevention and management.

Keywords

Aldehyde dehydrogenase 2 / Genetic polymorphism / Mendelian randomization / Stroke

References

[1] Hilkens NA, Casolla B, Leung TW, de Leeuw FE. Stroke. Lancet. 2024; 403(10446): 2820-2836. doi: 10.1016/s0140-6736(24)00642-1

[2] GBD 2021 Stroke Risk Factor Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024; 23(10): 973-1003. doi: 10.1016/S1474-4422(24)00369-7

[3] Tu WJ, Wang LD ; Special Writing Group of China Stroke Surveillance Report. China stroke surveillance report 2021. Mil Med Res. 2023; 10(1): 33. doi: 10.1186/s40779-023-00463-x

[4] Yousufuddin M, Young N. Aging and ischemic stroke. Aging (Albany NY). 2019; 11(9): 2542-2544. doi: 10.18632/aging.101931

[5] Rexrode KM, Madsen TE, Yu AYX, Carcel C, Lichtman JH, Miller EC. The impact of sex and gender on stroke. Circ Res. 2022; 130(4): 512-528. doi: 10.1161/CIRCRESAHA.121.319915

[6] O’Donnell MJ, Chin SL, Rangarajan S, et al; INTERSTROKE Investigators. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016; 388(10046): 761-775. doi: 10.1016/S0140-6736(16)30506-2

[7] Chrostek MR, Fellows EG, Crane AT, Grande AW, Low WC. Efficacy of stem cell-based therapies for stroke. Brain Res. 2019; 1722: 146362. doi: 10.1016/j.brainres.2019.146362

[8] Rodgers H, Bosomworth H, Krebs HI, et al. Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial. Lancet. 2019; 394(10192): 51-62. doi: 10.1016/S0140-6736(19)31055-4

[9] Cramer SC, Dodakian L, Le V, et al; National Institutes of Health StrokeNet Telerehab Investigators. Efficacy of home-based telerehabilitation vs in-clinic therapy for adults after stroke: a randomized clinical trial. JAMA Neurol. 2019; 76(9): 1079-1087. doi: 10.1001/jamaneurol.2019.1604

[10] Godecke E, Armstrong E, Rai T, et al; VERSE Collaborative Group. A randomized control trial of intensive aphasia therapy after acute stroke: the Very Early Rehabilitation for SpEech (VERSE) study. Int J Stroke. 2021; 16(5): 556-572. doi: 10.1177/1747493020961926

[11] Boehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circ Res. 2017; 120(3): 472-495. doi: 10.1161/CIRCRESAHA.116.308398

[12] Zhang H, Fu L. The role of ALDH2 in tumorigenesis and tumor progression: targeting ALDH2 as a potential cancer treatment. Acta Pharm Sin B. 2021; 11(6): 1400-1411. doi: 10.1016/j.apsb.2021.02.008

[13] Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev. 2014; 94(1): 1-34. doi: 10.1152/physrev.00017.2013

[14] Wang B, Wang J, Zhou S, et al. The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer’s disease in Chinese. J Neurol Sci. 2008; 268(1-2): 172-175. doi: 10.1016/j.jns.2007.12.006

[15] Chen CH, Wang WL, Hsu MH, Mochly-Rosen D. Alcohol consumption, ALDH2 polymorphism as risk factors for upper aerodigestive tract cancer progression and prognosis. Life (Basel). 2022; 12(3): 348. doi: 10.3390/life12030348

[16] He L, Deng T, Luo H. Aldehyde dehydrogenase 2 (ALDH2) polymorphism and the risk of alcoholic liver cirrhosis among East Asians: a meta-analysis. Yonsei Med J. 2016; 57(4): 879-884. doi: 10.3349/ymj.2016.57.4.879

[17] Gross ER, Zambelli VO, Small BA, Ferreira JC, Chen CH, Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant. Annu Rev Pharmacol Toxicol. 2015; 55: 107-127. doi: 10.1146/annurev-pharmtox-010814-124915

[18] Jiang Y, He J, Liu H, Xu Z. Association between ALDH2 rs671 polymorphism and risk of ischemic stroke: a protocol for systematic review and meta analysis. Medicine (Baltim). 2020; 99(21): e20206. doi: 10.1097/MD.0000000000020206

[19] Xu YL, Hu YY, Li JW, Zhou L, Li L, Niu YM. Aldehyde dehydrogenase 2 rs671G>A polymorphism and ischemic stroke risk in Chinese population: a meta-analysis. Neuropsychiatr Dis Treat. 2019; 15: 1015-1029. doi: 10.2147/NDT.S196175

[20] Sun S, He J, Zhang Y, et al. Genetic polymorphisms in the ALDH2 gene and the risk of ischemic stroke in a Chinese Han population. Oncotarget. 2017; 8(60): 101936-101943. doi: 10.18632/oncotarget.21803

[21] Cheng X, Xu J, Gu M, et al. Genetic variants in ALDH2 predict risk of ischemic stroke in a Chinese population. Gene. 2018; 678: 49-54. doi: 10.1016/j.gene.2018.08.002

[22] Hou JY, Zhong ZX, Deng QT, Liu SD, Lin LF. Association between the polymorphism of aldehyde dehydrogenase 2 gene and cerebral infarction in a Hakka population in Southern China. Biochem Genet. 2020; 58(2): 322-334. doi: 10.1007/s10528-020-09950-5

[23] Li QY, Zhao NM, Ma JJ, et al. ALDH2*2 allele is a negative risk factor for cerebral infarction in Chinese women. Biochem Genet. 2015; 53(9-10): 260-267. doi: 10.1007/s10528-015-9686-9

[24] Sung YF, Lu CC, Lee JT, et al. Homozygous ALDH2*2 is an independent risk factor for ischemic stroke in Taiwanese men. Stroke. 2016; 47(9): 2174-2179. doi: 10.1161/STROKEAHA.116.013204

[25] Panisello-Rosello A, Lopez A, Folch-Puy E, et al. Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury: an update. World J Gastroenterol. 2018; 24(27): 2984-2994. doi: 10.3748/wjg.v24.i27.2984

[26] Kander MC, Cui Y, Liu Z. Gender difference in oxidative stress: a new look at the mechanisms for cardiovascular diseases. J Cell Mol Med. 2017; 21(5): 1024-1032. doi: 10.1111/jcmm.13038

[27] Ramchandani VA, Bosron WF, Li TK. Research advances in ethanol metabolism. Pathol Biol (Paris). 2001; 49(9): 676-682. doi: 10.1016/s0369-8114(01)00232-2

[28] Dettling A, Skopp G, Graw M, Haffner HT. The influence of sex hormones on the elimination kinetics of ethanol. Forensic Sci Int. 2008; 177(2-3): 85-89. doi: 10.1016/j.forsciint.2007.11.002

[29] Ye Y, Lin Y, Haseba T, et al. Sex-and ALDH2-dependent differences in alcohol metabolism and psychomotor performance: a study in Han Chinese adults after binge drinking. Ann Med. 2025; 57(1): 2496798. doi: 10.1080/07853890.2025.2496798

[30] Zhang S, Luo W, Pan T, Xie J, Xu Z, Fang Y. ALDH2 rs671 polymorphism likely a risk factor for hemorrhagic stroke: a hospital-based study. Int J Gen Med. 2023; 16: 1471-1478. doi: 10.2147/IJGM.S409183

[31] Nagasawa H, Wada M, Arawaka S, et al. A polymorphism of the aldehyde dehydrogenase 2 gene is a risk factor for multiple lacunar infarcts in Japanese men: the Takahata Study. Eur J Neurol. 2007; 14(4): 428-434. doi: 10.1111/j.1468-1331.2007.01700.x

[32] Yao CT, Cheng CA, Wang HK, et al. The role of ALDH2 and ADH1B polymorphism in alcohol consumption and stroke in Han Chinese. Hum Genomics. 2011; 5(6): 569-576. doi: 10.1186/1479-7364-5-6-569

[33] Higuchi S, Matsushita S, Imazeki H, Kinoshita T, Takagi S, Kono H. Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet. 1994; 343(8899): 741-742. doi: 10.1016/s0140-6736(94)91629-2

[34] Shin C, Kwack K, Cho NH, Kim SH, Baik I. Sex-specific differences in the association of a common aldehyde dehydrogenase 2 gene polymorphism and alcohol consumption with stroke risk in a Korean population: a prospective cohort study. Nutr Res Pract. 2015; 9(1): 79-86. doi: 10.4162/nrp.2015.9.1.79

[35] Qu Y, Zhang HL, Yu LM, Sun Y, Wu HL, Chen YG. Aldehyde dehydrogenase 2 polymorphism as a protective factor for intracranial vascular stenosis in ischemic stroke in Han Chinese. Int J Neurosci. 2016; 126(4): 342-347. doi: 10.3109/00207454.2015.1017760

[36] Qu Y, Zhang H, Li H, Yu L, Sun Y, Chen Y. Aldehyde dehydrogenase 2 (ALDH2) glu504Lys polymorphism affects collateral circulation and short-term prognosis of acute cerebral infarction patients. Med Sci Monit. 2017; 23: 4559-4566. doi: 10.12659/msm.905206

[37] Yu Y, Gao J, Wang S, et al. Synergistic effects of aldehyde dehydrogenase 2 polymorphisms and alcohol consumption on cognitive impairment after ischemic stroke in Han Chinese. Behav Neurol. 2021; 2021: 6696806. doi: 10.1155/2021/6696806

[38] Yang H, Song Z, Yang GP, et al. The ALDH2 rs671 polymorphism affects post-stroke epilepsy susceptibility and plasma 4-HNE levels. PLoS One. 2014; 9(10): e109634. doi: 10.1371/journal.pone.0109634

[39] Guo JM, Liu AJ, Zang P, et al. ALDH2 protects against stroke by clearing 4-HNE. Cell Res. 2013; 23(7): 915-930. doi: 10.1038/cr.2013.69

[40] Lee WC, Wong HY, Chai YY, et al. Lipid peroxidation dysregulation in ischemic stroke: plasma 4-HNE as a potential biomarker? Biochem Biophys Res Commun. 2012; 425(4): 842-847. doi: 10.1016/j.bbrc.2012.08.002

[41] Wang W, Lin LL, Guo JM, et al. Heavy ethanol consumption aggravates the ischemic cerebral injury by inhibiting ALDH2. Int J Stroke. 2015; 10(8): 1261-1269. doi: 10.1111/ijs.12560

[42] Fu SH, Zhang HF, Yang ZB, et al. Alda-1 reduces cerebral ischemia/reperfusion injury in rat through clearance of reactive aldehydes. Naunyn Schmiedebergs Arch Pharmacol. 2014; 387(1): 87-94. doi: 10.1007/s00210-013-0922-8

[43] Li Y, Liu SL, Qi SH. ALDH2 protects against ischemic stroke in rats by facilitating 4-HNE clearance and AQP4 down-regulation. Neurochem Res. 2018; 43(7): 1339-1347. doi: 10.1007/s11064-018-2549-0

[44] Mao L, Zuo ML, Hu GH, Duan XM, Yang ZB. mir-193 targets ALDH2 and contributes to toxic aldehyde accumulation and tyrosine hydroxylase dysfunction in cerebral ischemia/reperfusion injury. Oncotarget. 2017; 8(59): 99681-99692. doi: 10.18632/oncotarget.21129

[45] Liu L, Deng Q, Xie L, et al. ALDH2 overexpression improves the blood-brain barrier and represses mitochondrial dysfunction in chronic cerebral hypoperfusion through the SIRT1/ROS axis. Neurochem Res. 2025; 50(2): 102. doi: 10.1007/s11064-025-04353-7

[46] Xia P, Zhang F, Yuan Y, et al. ALDH 2 conferred neuroprotection on cerebral ischemic injury by alleviating mitochondria-related apoptosis through JNK/caspase-3 signing pathway. Int J Biol Sci. 2020; 16(8): 1303-1323. doi: 10.7150/ijbs.38962

[47] Lin L, Tao JP, Li M, et al. Mechanism of ALDH2 improves the neuronal damage caused by hypoxia/reoxygenation. Eur Rev Med Pharmacol Sci. 2022; 26(8): 2712-2720. doi: 10.26355/eurrev_202204_28601

[48] Qu Y, Liu Y, Zhang H. ALDH2 activation attenuates oxygen-glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. Clin Transl Oncol. 2023; 25(11): 3203-3216. doi: 10.1007/s12094-023-03190-w

[49] Liu XZ, Sun X, Shen KP, et al. Aldehyde dehydrogenase 2 overexpression inhibits neuronal apoptosis after spinal cord ischemia/reperfusion injury. Neural Regen Res. 2017; 12(7): 1166-1171. doi: 10.4103/1673-5374.211198

[50] Diao M, Xu J, Wang J, et al. Alda-1, an activator of ALDH2, improves postresuscitation cardiac and neurological outcomes by inhibiting pyroptosis in swine. Neurochem Res. 2022; 47(4): 1097-1109. doi: 10.1007/s11064-021-03511-x

[51] Zhang T, Huang L, Peng J, Zhang JH, Zhang H. LJ529 attenuates mast cell-related inflammation via A(3)R-PKCepsilon-ALDH2 pathway after subarachnoid hemorrhage in rats. Exp Neurol. 2021; 340: 113686. doi: 10.1016/j.expneurol.2021.113686

[52] Nene A, Chen CH, Disatnik MH, Cruz L, Mochly-Rosen D. Aldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites. J Biomed Sci. 2017; 24(1): 3. doi: 10.1186/s12929-016-0312-x

[53] Georgakis MK, Gill D. Mendelian randomization studies in stroke: exploration of risk factors and drug targets with human genetic data. Stroke. 2021; 52(9): 2992-3003. doi: 10.1161/STROKEAHA.120.032617

[54] Cho Y, Lin K, Lee SH, et al; China Kadoorie Biobank Collaborative Group. Genetic influences on alcohol flushing in East Asian populations. BMC Genomics. 2023; 24(1): 638. doi: 10.1186/s12864-023-09721-7

[55] Millwood IY, Walters RG, Mei XW, et al; China Kadoorie Biobank Collaborative Group. Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China. Lancet. 2019; 393(10183): 1831-1842. doi: 10.1016/S0140-6736(18)31772-0

[56] Hu C, Huang C, Li J, et al. Causal associations of alcohol consumption with cardiovascular diseases and all-cause mortality among Chinese males. Am J Clin Nutr. 2022; 116(3): 771-779. doi: 10.1093/ajcn/nqac159

[57] Hisamatsu T, Tabara Y, Kadota A, et al. Alcohol consumption and cerebral small-and large-vessel diseases: a Mendelian randomization analysis. J Atheroscler Thromb. 2024; 31(2): 135-147. doi: 10.5551/jat.64222

[58] Yao P, Mazidi M, Pozarickij A, et al; China Kadoorie Biobank Collaborative Group. Proteome-wide genetic study in East Asians and Europeans identified multiple therapeutic targets for ischemic stroke. Stroke. 2025; 56(8): 2147-2158. doi: 10.1161/STROKEAHA.125.050982

[59] Zhang C, Qin F, Li X, Du X, Li T. Identification of novel proteins for lacunar stroke by integrating genome-wide association data and human brain proteomes. BMC Med. 2022; 20(1): 211. doi: 10.1186/s12916-022-02408-y

[60] Yang XZ, Huang MY, Han F, et al. Genome-wide Mendelian randomization study reveals druggable genes for cerebral small vessel disease. Stroke 2024; 55(9): 2264-2273. doi: 10.1161/STROKEAHA.124.046544

[61] Liu Y, Wang W, Cui X, Lyu J, Xie Y. Exploring genetic associations of 3 types of risk factors with ischemic stroke: an integrated bioinformatics study. Stroke. 2024; 55(6): 1619-1628. doi: 10.1161/STROKEAHA.123.044424

[62] Fan M, Li N, Huang L, Chen C, Dong X, Gao W. Exploring potential drug targets in multiple cardiovascular diseases: a study based on proteome-wide Mendelian randomization and colocalization analysis. Cardiovasc Ther. 2025; 2025: 5711316. doi: 10.1155/cdr/5711316

[63] Tang J, Alford A, Leung G, Tully M, Shi R. Neuroprotection by acrolein sequestration through exogenously applied scavengers and endogenous enzymatic enabling strategies in mouse EAE model. Sci Rep. 2024; 14(1): 6027. doi: 10.1038/s41598-024-56035-z

[64] Yang P, Su W, Wang L, Xu F, Kong Y, Long J. From aldehyde metabolism to delay aging: targeting ALDH2 as a novel strategy. Free Radic Biol Med. 2025; 236: 70-86. doi: 10.1016/j.freeradbiomed.2025.05.389

[65] Matsumura Y, Stiles KM, Reid J, et al. Gene therapy correction of aldehyde dehydrogenase 2 deficiency. Mol Ther Methods Clin Dev. 2019; 15: 72-82. doi: 10.1016/j.omtm.2019.08.004

[66] Chen M, Mao A, Xu M, Weng Q, Mao J, Ji J. CRISPR-Cas9 for cancer therapy: opportunities and challenges. Cancer Lett. 2019; 447: 48-55. doi: 10.1016/j.canlet.2019.01.017

[67] Tang R, Xu Z. Gene therapy: a double-edged sword with great powers. Mol Cell Biochem. 2020; 474(1-2): 73-81. doi: 10.1007/s11010-020-03834-3

[68] Anguela XM, High KA. Entering the modern era of gene therapy. Annu Rev Med. 2019; 70: 273-288. doi: 10.1146/annurev-med-012017-043332