Effects of APOE ε2 on the Fractional Amplitude of Low-Frequency Fluctuation in Mild Cognitive Impairment: A Study Based on the Resting-State Functional MRI.

Xiaocao Liu,Shuyue Wang,Xiaojun Guan,Peiyu Huang,Tianyi Zhang,Xiaojun Xu,Minming Zhang,Qingze Zeng,Yanv Fu,Zheyu Li,Xiao Luo,Jingjing Wu,Chao Wang,Ruiting Zhang,Tao Wang,Kaicheng Li,Hui Hong

doi:10.3389/fnagi.2021.591347

Abstract

BackgroundApolipoprotein E (APOE) ε2 is a protective genetic factor for Alzheimer’s disease (AD). However, the potential interaction effects between the APOE ε2 allele and disease status on the intrinsic brain activity remain elusive.MethodsWe identified 73 healthy control (HC) with APOE ε3/ε3, 61 mild cognitive impairment (MCI) subjects with APOE ε3/ε3, 24 HC with APOE ε2/ε3, and 10 MCI subjects with APOE ε2/ε3 from the ADNI database. All subjects underwent a resting-state functional MRI and Fluoro-deoxy-glucose positron emission tomography (FDG-PET). We used a fractional amplitude of low-frequency fluctuation (fALFF) to explore the spontaneous brain activity. Based on the mixed-effects analysis, we explored the interaction effects between the APOE ε2 allele versus disease status on brain activity and metabolism in a voxel-wise fashion (GRF corrected, p < 0.01), followed by post hoc two-sample t-tests (Bonferroni corrected, p < 0.05). We then investigated the relationship between the mean imaging metrics and cognitive abilities.ResultsThere are no significant differences in gender, age, or education among the four groups. The interaction effect on brain activity was located in the inferior parietal lobule (IPL). Post hoc analysis showed that APOE ε2/ε3 MCI had an increased IPL fALFF than APOE ε3/ε3 MCI. Regarding the APOE ε2 allele effects, we found that ε2 carriers had a decreased fALFF in the transverse temporal gyrus than non-carriers. Also, FDG-PET results showed a lower SUVR of the frontal lobe in APOE ε2 carriers than non-carriers. Furthermore, fALFF of IPL was correlated with the visuospatial function (r = −0.16, p < 0.05).ConclusionAPOE ε2 carriers might have a better brain reservation when coping with AD-related pathologies.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia and is usually clinically characterized by a progressive and irreversible cognitive decline
Post hoc analysis showed that Apolipoprotein E (APOE) ε2/ε3 mild cognitive impairment (MCI) had an increased inferior parietal lobule (IPL) fractional amplitude of low-frequency fluctuation (fALFF) than APOE ε3/ε3 MCI
Regarding the APOE ε2 allele effects, we found that ε2 carriers had a decreased fALFF in the transverse temporal gyrus than non-carriers

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia and is usually clinically characterized by a progressive and irreversible cognitive decline. APOE ε4 and ε2 are risks and protective factors for AD, respectively (Corder et al, 1993; McKenna et al, 2016). Past epidemiological studies revealed that the risk for APOE ε2 homozygous carriers to develop AD is four times lower than that of a healthy elderly carrying APOE ε4 (Corder et al, 1994). While accumulated evidence shows that the APOE ε2 allele plays a protective role in AD, some studies proposed relatively conservative ideas. One pathological study showed that the APOE ε2 allele was associated with large but circumscribed protective effects (Goldberg et al, 2020). Apolipoprotein E (APOE) ε2 is a protective genetic factor for Alzheimer’s disease (AD). The potential interaction effects between the APOE ε2 allele and disease status on the intrinsic brain activity remain elusive

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Discussion

Conclusion