Common human ALDH1B1 and ALDH2 variants increase neuroinflammatory response to a single ethanol dose in mice

Unlike the well-documented effects of aldehyde dehydrogenase 2 (ALDH2) hypoactive variants, the impact of hypoactive ALDH1B1 has yet to be elucidated. Using the Global Human Genome Aggregation Database, we identified 38 ALDH1B1 variants, common (>0.1% allele frequency) to different human genetic ancestral groups. Some missense ALDH1B1 human variants are notably less active and less stable, and three variants represent a complete loss of function (LoF) due to early stop codon. Since these inactive variants are common among humans, we studied the impact of carrying both ALDH1B1 LoF and ALDH2 inactive variant in mice. Double knock-in (DKI) mice carrying ALDH1B1^G193fs and ALDH2*2^E504K exhibited elevated neuroinjury markers. Following a single ethanol gavage (2 grams per kilogram), DKI mice showed exacerbated intoxication and significantly higher levels of neuroinjury markers, including elevated amyloid-β and ptau217 compared to WT or single-mutant mice. Our study highlights a potential impact of common hypoactive mitochondrial ALDH enzymes on human health, especially among those that consume alcohol.