Hepatic expression of APOE3 Christchurch mitigates APOE4-related Alzheimer's disease pathologies in mice

The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.