Asian flush gene variant increases mild cognitive impairment risk: a cross-sectional study of the Yoshinogari Brain MRI Checkup Cohort

Abstract

Background: The East Asian-specific genetic diversity, the rs671 variant of aldehyde dehydrogenase 2, causes the "Asian flush" phenomenon following alcohol consumption, resulting in an alcohol avoidance phenotype. The variant is suggested as a risk factor for Alzheimer's disease; however, its association with mild cognitive impairment (MCI), an effective target for secondary prevention of dementia, remains unclear.

Method: This cross-sectional study examined 430 individuals aged 60-80 years (251 women) without overt cognitive impairment in Yoshinogari, Japan. The effect of the rs671 variant on MCI, defined by scores <26 or <25 on the Japanese version of the Montreal Cognitive Assessment, was evaluated using multivariate logistic regression.

Results: The models included APOEε4, sex, age, education, history of habitual drinking, Brinkman index, hypertension, diabetes, and subclinical magnetic resonance imaging findings and consistently estimated the risk of the rs671 variant. Subsequently, stratified analyses by history of habitual drinking were performed based on an interactive effect between rs671 and alcohol consumption, and the rs671 variant significantly influenced MCI in participants who did not drink habitually, with odds ratios ranging from 1.9 to 2.1 before and after adjusting for covariates, suggesting an association independent of hippocampal atrophy and small vessel dysfunction. Conversely, no such association with the rs671 variant was observed in participants with a history of habitual alcohol use. Instead, hippocampal atrophy and silent infarcts were associated with MCI.

Conclusions: This is the first study to demonstrate an association between the rs671 variant and MCI morbidity. The findings highlight the need for race-specific preventive strategies and suggest potential unrecognized mechanisms in dementia development.

Keywords: Aldehyde dehydrogenase 2; Dementia; Mild cognitive impairment (MCI); Prevention; Race; rs671.

Fig. 1

Association between ALDH2 rs671 variant and mild cognitive impairment A) Distribution of MoCA-J scores by ALDH2 rs671 genotypes for the total cohort (N = 430) and stratified cohorts by a history of habitual alcohol consumption, 0 year (N = 250) or >0 year (N = 175), where unknown drinking history was removed from (N = 5). Error bars indicate the median and interquartile range. The gray-shaded area represents MCI (MoCA-J < 26). The MCI rate is shown in the panel. B) Odds ratios for mild cognitive impairment defined by MoCA-J < 26 stratified by a history of habitual drinking. All covariates used in the modeling are shown. Akaike Information Criterion (smaller values indicate better model fit) in each model was 301, 263, 256, and 271 for Crude, Model A, Model B, and Model C, respectively, for the “0-year” stratum, and similarly, 235, 228, 225, and 225 for the “>0 years” stratum. C) Interaction between the rs671 variant and history of habitual drinking. Odds ratios were estimated using Model 2 in Table S3 with categorizations modified as indicated in the panel.