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

Yan-Li Wang; Mengfan Sun; Fang-Ze Wang; Xiaohong Wang; Ziyan Jia; Yuan Zhang; Runzhi Li; Jiwei Jiang; Linlin Wang; Wenyi Li; Yongan Sun; Jinglong Chen; Cuicui Zhang; Baolin Shi; Jianjian Liu; Xiangrong Liu; Jun Xu

doi:10.3389/fnagi.2022.928925

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

Front Aging Neurosci. 2022 Jun 30:14:928925. doi: 10.3389/fnagi.2022.928925. eCollection 2022.

Authors

Yan-Li Wang^{1

2}, Mengfan Sun¹, Fang-Ze Wang³, Xiaohong Wang⁴, Ziyan Jia¹, Yuan Zhang¹, Runzhi Li¹, Jiwei Jiang¹, Linlin Wang¹, Wenyi Li¹, Yongan Sun⁵, Jinglong Chen⁶, Cuicui Zhang⁷, Baolin Shi⁸, Jianjian Liu⁹, Xiangrong Liu², Jun Xu^{1

2}

Affiliations

¹ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
² China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
³ Department of Cardiology, Weifang People's Hospital, Weifang Medical University, Weifang, China.
⁴ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
⁵ Department of Neurology, Peking University First Hospital, Peking University, Beijing, China.
⁶ Division of Neurology, Department of Geriatrics, National Clinical Key Specialty, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
⁷ Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
⁸ Department of Neurology, Weifang People's Hospital, Weifang Medical University, Weifang, China.
⁹ Department of Neurology, Fuxing Hospital, Capital Medical University, Beijing, China.

Abstract

Background: The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between ε4 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 ε4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects.

Result: APOE ε4 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 ε4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.

Keywords: APOE ε4; CIBL study; causal mediation; cerebral blood flow; cognition.