The Aldehyde Dehydrogenase 2*2 (ALDH2*2) polymorphism “Asian Flush,” impairs aldehyde detoxification and is a significant risk factor for Alzheimer’s disease (AD). Concurrently, the apolipoprotein E (APOE) ε4 allele represents the major genetic risk for AD and is implicated in metabolic dysfunction and oxidative stress – pathways also compromised by ALDH2 deficiency.

We hypothesize that ALDH2 deficiency disrupts metabolic homeostasis, creating a circadian misalignment that amplifies the impact of environmental stressors, including circadian disruption (CD), a vulnerability potentially exacerbated by APOE4 status in the aging brain.

ALDH2 Het mice maintained significantly higher body temperature. In LD, Hets showed reduced rhythm robustness (lower amplitude and amplitude).

In DD, temperature rhythms in Hets exhibited increased fragmentation (higher IV) and a longer period, indicating central clock dysfunction.

Under CD, Hets have more activity and higher body temperature. 

Male Hets developed pronounced anxiety and spatial working memory deficits.

IntelliCage analysis of APOE4 carriers revealed distinct circadian activity shifts that precede cognitive deficits, contrasting with initially preserved spatial memory.

Under CD, double-mutant lines exhibit sex-specific susceptibility to circadian disruption.

Female ADE4 mice develop pronounced compulsive-like phenotypes and global cognitive deficits (context and cued fear conditioning).

•ALDH2 deficiency compromises circadian resilience, thermoregulation, and working memory.

Future steps include multi-omics analysis to identify the metabolic and cellular pathways underpinning the circadian and cognitive alterations induced by ALDH2*2 and APOE4 genotypes

Funding support: AARFD-23-1150996, R01 AA028081-01 and 23AARG-1019127

Contact: danielm6@usf.edu