Mediation of the APOE Associations With Cognition Through Cerebral Blood Flow: The CIBL Study

Background: The epsilon 4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between epsilon 4 alleles and cognition is not well understood. The objective of this study was to identify the roles of cerebral blood flow (CBF) in cognitive-related brain areas in mediating the associations of APOE with cognition. Methods: The multiple linear regression analyses were conducted on 369 subjects (mean age of 68.8 years; 62.9% of women; 29.3% of APOE epsilon 4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects. Result: APOE epsilon 4 allele was negatively associated with cognition (P < 0.05) and CBF in the amygdala, hippocampus, middle temporal gyrus, posterior cingulate, and precuneus (all P < 0.05). The effect of the APOE genotype on cognition was partly mediated by the above CBF (all P < 0.05). Conclusion: CBF partially mediates the potential links between APOE genotype and cognition. Overall, the APOE epsilon 4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.