A recent Nature Communications study finds that the East Asian-prevalent ALDH2*2 variant (rs671) linked to alcohol flush reaction promotes Alzheimer’s disease (AD) by increasing Aβ plaque deposition, disrupting Aβ40/42 balance, and impairing microglial clearance. Mechanistically, ALDH2 dysfunction causes toxic aldehyde 4-HNE accumulation, altering APP processing and neuroinflammatory defenses, identifying it as a key AD risk factor with therapeutic potential.
The ALDH2*2 Variant: A Genetic Predisposition with Multifaceted Health Implications
In East Asian populations, approximately 36% of individuals carry the ALDH2*2 (rs671) single-nucleotide polymorphism, which results from a c.487G>A substitution leading to a Glu487Lys amino acid change in the ALDH2 enzyme. This mutation profoundly impairs enzymatic activity: homozygous (AA) individuals exhibit less than 6% of wild-type ALDH2 activity, while heterozygous (GA) carriers retain only ~40% functionality. The functional deficit manifests most obviously as the alcohol flush reaction, where acetaldehyde accumulation within 15–30 minutes of alcohol intake triggers vasodilation, facial reddening, and tachycardia.
While acetaldehyde-induced flushing is the variant’s most recognizable effect, ALDH22 also disrupts the metabolism of 4-hydroxy-2-nonenal (4-HNE), a reactive aldehyde generated during lipid peroxidation. In wild-type cells, ALDH2 efficiently oxidizes 4-HNE to 4-hydroxy-2-nonenoic acid (4-HNA), but the rs671 mutation reduces this activity by 72%. Consequently, fibroblasts from ALDH22 carriers show 2.3-fold higher 4-HNE levels, promoting widespread protein carbonylation and DNA damage. This dual defect in aldehyde metabolism—affecting both alcohol-derived acetaldehyde and endogenously produced 4-HNE—sets the stage for systemic oxidative stress, particularly in organs with high alcohol exposure or metabolic activity, such as the brain.
ALDH2*2 and Alzheimer’s Pathology: Insights from Human and Preclinical Studies
Postmortem Brain Bank Analyses
The study leveraged 469 postmortem brain samples from the Chinese National Human Brain Bank, spanning individuals with ALDH2 genotypes GG (wild-type), GA (heterozygous), and AA (homozygous).
Pathological analysis revealed striking differences in Aβ burden: Bielschowsky silver staining showed that AA carriers had 2.1-fold higher Aβ plaque density in the entorhinal cortex compared to GG individuals (p=0.008). Biochemical analyses further demonstrated that Aβ40 levels were 1.68-fold elevated in AA brains, while Aβ42 concentrations dropped by 32% (p<0.01).
The Aβ40/42 ratio, a critical marker of AD risk, correlated inversely with ALDH2 activity (Pearson r=−0.41, p<0.001), with AA carriers facing a 3.35-fold increased risk of having a ratio exceeding 12 (odds ratio=3.35, 95% confidence interval=1.25–8.98). These findings held true even after adjusting for age, sex, and APOE ε4 status, underscoring ALDH2*2 as an independent risk factor.
Figure 1. Correlation between ALDH2 rs671 variant and Aβ pathology
Preclinical Validation in Mouse Models
To mechanistically validate these observations, researchers used Aldh2 knockout (Aldh2−/−) mice crossed with APP/PS1 transgenic mice, a well-characterized model of AD. Treating these mice with daidzin (150 mg/kg/day intraperitoneally) for two months—an ALDH2 inhibitor that mimics the rs671 phenotype—yielded striking results: ELISA analyses showed 1.48-fold higher cortical Aβ40 levels (p=0.023) and 1.83-fold higher hippocampal Aβ40 (p=0.015) in daidzin-treated mice.
Immunohistochemical staining revealed a 62% reduction in microglial clustering around Aβ plaques, as assessed by Iba1 immunoreactivity. Intravital two-photon microscopy further demonstrated that 4-HNE fluorescence, detected using a specific probe, was 2.7-fold higher in Aldh2−/− APP/PS1 brains compared to wild-type APP/PS1 mice (p<0.001), with significant colocalization with Aβ deposits labeled by the 6E10 antibody. These findings established a clear link between ALDH2 dysfunction, 4-HNE accumulation, and exacerbated Aβ pathology in vivo.
Molecular Mechanisms: From Aldehyde Stress to Neurodegeneration
A key mechanistic insight came from the discovery that 4-HNE covalently modifies the C99 fragment of the amyloid precursor protein (APP). Mass spectrometry identified 4-HNE bound to Lys53 of C99 (residues 597–695 of APP), a modification confirmed by immunoblotting with a 4-HNE-specific antibody. Circular dichroism spectroscopy revealed that 4-HNE modification induced a 21% increase in β-sheet content within C99, altering its conformation to favor γ-secretase cleavage at Val40 over Ala42. In cell-free cleavage assays, 4-HNE-modified C99 led to a 1.47-fold increase in the Aβ40/42 ratio (p=0.003), directly explaining the altered peptide balance observed in ALDH2*2 carriers.
Figure 2. Effect of ALDH2 activity on Aβ40/42 ratio
Further investigations into APP trafficking revealed that 4-HNE promotes APP retention in the Golgi apparatus. Immunoelectron microscopy showed a 1.8-fold higher density of APP in Golgi cisternae of ALDH22 cells compared to wild-type cells. Co-immunoprecipitation experiments demonstrated that 4-HNE enhanced the interaction between APP and the sorting receptor SORL1 by 2.3-fold (p<0.01), a key step in blocking retrograde transport via COPI vesicles. siRNA knockdown of SORL1 rescued APP Golgi retention in ALDH22 cells, reducing accumulation by 68% (p<0.05), which confirmed the critical role of this pathway in mediating 4-HNE’s effects on APP processing.
Compromised Microglial Function: A Secondary Hit in ALDH2*2 Brains
ALDH2 dysfunction not only promotes Aβ production but also impairs the brain’s primary defense against Aβ aggregates: microglial phagocytosis. In BV2 microglial cells treated with daidzin (10 μM), flow cytometry revealed a 52% reduction in Aβ42 phagocytosis (p<0.001). RNA-seq analyses identified downregulation of key phagocytosis genes, including CD36 and TREM2, by 1.7–2.1-fold in daidzin-treated microglia, providing a transcriptional basis for the functional deficit.
Figure 5. Effect of reduced ALDH2 activity on microglial function
Mechanistic studies of inflammatory signaling showed that ALDH22 microglia exhibited impaired NF-κB activation, with p65 nuclear translocation reduced by 41% (p=0.009). Cytokine array analyses detected 38% lower TNF-α and 29% lower IL-1β secretion in response to Aβ42 stimulation (p<0.05), indicating a broader defect in proinflammatory signaling that may compromise the microglial response to Aβ plaques. These combined deficits in phagocytosis and inflammation create a permissive environment for Aβ accumulation and plaque expansion in ALDH22 brains.
Broader Genetic and Epidemiological Context
9Global Distribution and Genetic Interactions
While ALDH22 is most prevalent in East Asian populations (36%), it is also present in Europeans (4%), Africans (1.2%), and Native Americans (2.8%). In genome-wide association studies of East Asian populations, ALDH22 accounts for 3.7% of AD genetic risk, making it a significant contributor alongside APOE ε4, which explains 24% of risk. Notably, the variant exhibits a gene-gene interaction with APOE, with ALDH2*2 carriers also carrying APOE ε4 showing a synergistic 7.1-fold increased AD risk compared to non-carriers of either variant (95% CI=3.4–14.9, p<0.001). This interaction highlights the complexity of AD pathogenesis and the need for multi-marker risk assessment in clinical settings.
Conclusion
The ALDH22 variant emerges as a pivotal genetic factor connecting alcohol metabolism, aldehyde-induced oxidative stress, and Alzheimer’s disease pathogenesis. Its dual impact—promoting Aβ production through 4-HNE-modified APP processing and disabling microglial clearance mechanisms—creates a unique vulnerability for neurodegeneration. For the millions of East Asians carrying this variant, the facial flush reaction to alcohol serves as a tangible warning sign of underlying biological risks.
Beyond immediate discomfort, it signals a need for proactive neurological protection, starting with strict alcohol abstinence. As our understanding of the ALDH22-AD link deepens, personalized prevention strategies targeting aldehyde metabolism may offer hope for mitigating this significant yet modifiable risk factor. The journey from a visible genetic phenotype to its underlying molecular consequences exemplifies how basic research on a seemingly trivial trait can unlock new paradigms in disease prevention and treatment.
Reference
Wang X, Wang J, Chen Y, et al. The aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology. Nat Commun. 2024;15(1):2594. doi:10.1038/s41467-024-46899-0