Apolipoprotein E Induced Cognitive Dysfunction: Mediation Analysis of Lipids and Glucose Biomarkers in an Elderly Cohort Study.

Linxin Liu,Andy J Liu,Hari Iyer,Huichu Li,Yi Zeng,John S Ji

doi:10.3389/fnagi.2021.727289

Abstract

IntroductionPrior evidence suggested Apolipoprotein E (APOE), lipids, and glucose metabolism may act through the same pathways on the pathogenesis of Alzheimer’s disease (AD).MethodsThis prospective study used data from the Chinese Longitudinal Healthy Longevity Study. We tested the associations of APOE genotype (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, and ε4ε4) and cognitive function using generalized estimating equations (GEE). We examined for possible mediation and effect modification by lipids and glucose level in this association.ResultsAPOE ε2 showed significant direct protective effect and indirect harmful effect through TC on cognitive function. Abnormal lipids or glucose levels were not consistently associated with cognitive dysfunction in our study. We did not detect significant indirect effects through lipids for APOE ε4 or any indirect effects through glucose.DiscussionThese findings suggested complicated relationships among APOE, lipids, glucose, and cognitive function. Further study can make validations in other populations.

Highlights

Prior evidence suggested Apolipoprotein E (APOE), lipids, and glucose metabolism may act through the same pathways on the pathogenesis of Alzheimer’s disease (AD)
A meta-analysis of 141 articles covering European, North American, and East Asian population demonstrated that APOE genotype had a positive association with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels when ordered as ε2/ε2, ε2/ε3, ε2/ε4, APOE, Lipids, Glucose and Cognition ε3/ε3, ε3/ε4 and ε4/ε4 (Bennet et al, 2007)
We found a protective effect of APOE ε2 on cognitive function, which was mediated by TC and LDL-C in a suppressive way (Conger, 1974)

Summary

Introduction

Prior evidence suggested Apolipoprotein E (APOE), lipids, and glucose metabolism may act through the same pathways on the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) gene is a well-established susceptibility gene for the development of lateonset Alzheimer’s disease (AD). The APOE gene could affect neurodegeneration through multiple pathways, including neurite remodeling, glutamate receptor function, and synaptic plasticity modulation, and cholesterol redistribution (Huang and Mucke, 2012). A meta-analysis of 141 articles covering European, North American, and East Asian population demonstrated that APOE genotype had a positive association with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels when ordered as ε2/ε2, ε2/ε3, ε2/ε4, APOE, Lipids, Glucose and Cognition ε3/ε3, ε3/ε4 and ε4/ε4 (Bennet et al, 2007). The effects of APOE polymorphism may act through some of the same mechanisms as the disruption of homeostasis in lipid and glucose metabolism in the pathogenesis of AD (Shinohara and Sato, 2019)

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