The Specific Impact of Apolipoprotein E Epsilon 2 on Cognition and Brain Function in Cognitively Normal Elders and Mild Cognitive Impairment Patients.

Bei Zhang,Ronghua Xu,Liang Gong,Chuantao Zhang,Duan Liu,Lin Lan

doi:10.3389/fnagi.2019.00374

Bei Zhang, Ronghua Xu + Show 4 more

Open Access

https://doi.org/10.3389/fnagi.2019.00374

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Abstract

Variants in the apolipoprotein E (APOE) gene play an important role in the development of Alzheimer’s disease (AD). Specifically, the APOE ε4 allele is an established genetic risk factor for AD, while the APOE ε2 allele is a protective factor against AD. However, the mechanism underlying this impact of APOE genotype on the pathogenesis of AD remain unclear. This study sought to investigate the influence of APOE genotype on cognition and neuroimaging features in cognitively normal (CN) elderly individuals and patients with mild cognitive impairment (MCI). A total of 177 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, including 101 MCI patients and 76 CN individuals. A 2 × 3 (consisting of two groups and three APOE genotypes) analysis of covariance was carried out to measure the influences of diagnosis and APOE genotype on cognition and brain features, assessed based on global functional connectivity density (gFCD) and hippocampal volume. In addition, a mediation analysis was carried out to investigate the indirect influence of neuroimaging features on the relationship between APOE genotype and cognitive performance in the MCI group. This analysis revealed that APOE genotype had an influence on brain function in the bilateral precentral gyrus, right thalamus, and posterior cingulate cortex (PCC). In addition, an interactive influence between diagnosis and APOE genotype was found on general cognition, immediate memory, executive function, hippocampal volume, and gFCD in the right dorsolateral prefrontal cortex and medial prefrontal cortex (MPFC). Finally, this mediation analysis revealed that hippocampal volume and gFCD in the thalamus may mediate the relationship between APOE genotype and cognitive performance in the MCI group. Taken together, our findings provide novel insights into the neural mechanisms underlying the genetically guided pathogenic mechanisms of AD.

Highlights

Apolipoprotein E (APOE) is a major genetic risk factor contributing to the development of late-onset Alzheimer’s disease (AD)
We investigated the impact of the apolipoprotein E (APOE) genotype (ε2+, ε3/ε3, and ε4+) and its interaction with disease status on cognitive function, hippocampal volume, and global functional connectivity density (gFCD) in cognitively normal (CN) elderly and mild cognitive impairment (MCI) patients
There were no significant differences in age, sex, and years of education between the CN and MCI groups with different APOE genotypes

Summary

Introduction

Apolipoprotein E (APOE) is a major genetic risk factor contributing to the development of late-onset Alzheimer’s disease (AD). The neuropathological mechanism underlying the opposite outcomes on cognitive function is still unclear. In the last few decades, many studies investigated the impact of APOE genotype variations on brain structure and function in individuals with AD or mild cognitive impairment (MCI) and healthy elders using neuroimaging and genetic analysis (Spampinato et al, 2011; Troyer et al, 2012; Wang et al, 2015). Most of the studies focused on the neural basis of the APOE ε4 allele and investigated the group differences in brain structure and function between ε4 and non-ε4 carriers. Because of the relative rarity of the ε2 allele, studies examining the influences of the APOE ε2 allele on the neuropathology of AD are still lacking, and the mechanisms underlying the impact of the ε2 allele on AD development remain unclear (Suri et al, 2013)

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