Abstract
ObjectiveTo investigate the impact of Alzheimer’s disease (AD)-related risk gene (ATP-binding cassette A7-ABCA7 and Clusterin-CLU) on the functional connectivity pattern of default mode network (DMN) in healthy middle-age adults.MethodsA total of 147 healthy middle-aged volunteers were enrolled in this study. All subjects completed MRI scans, neuropsychological assessments, and AD-related genotyped analysis. All subjects were divided into high, middle and low risk groups according to the score of risk genotypes, which included CLU (rs11136000, rs2279590, rs9331888, and rs9331949) and ABCA7 (rs3764650 and rs4147929). The genetic effects of CLU, ABCA7, and CLU × ABCA7 on DMN functional connectivity pattern were further explored. Moreover, the genetic effect of Apolipoprotein ε4 (APOEε4) was also considered. Finally, correlation analysis was performed between the signals of brain regions with genetic effect and neuropsychological test scores.ResultsCompared with the low-risk group, the high-risk group of CLU showed decreased functional connectivity in posterior cingulate cortex (PCC) and the left middle frontal cortex (P < 0.05, GRF correction). As for the interaction between the CLU and ABCA7, all the subjects were divided into high, middle, and low risk group; the middle-risk group was divided into CLU and ABCA7-dominated middle-risk group. The function connectivity pattern of DMN among the three or four groups were distributed in the bilateral medial prefrontal cortex (MPFC) and bilateral superior frontal gyrus (SFG) (P < 0.05, GRF correction). When APOEε4 carriers were excluded, the CLU-predominant middle-risk group displayed the decreased functional connectivity in MPFC when compared with the low-risk group, while ABCA7-prodominant middle-risk group displayed decreased functional connectivity in cuneus when compared with the high-risk group (all P < 0.05, GRF correction). The z values of left middle frontal cortex were positively correlated with the scores of Serial Dotting Test (SDT) in high-risk group of CLU, while z values of MPFC and cuneus were positively correlated to the scores of Montreal Cognitive Assessment (MoCA) in low-risk group of three or four groups.ConclusionThe functional connectivity of MPFC-PCC might be modulated by the interaction of CLU and ABCA7. Moreover, APOEε4 might be interacted with ABCA7 and CLU modulation in the middle-aged carriers.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease with complex genetic characteristics (Lane et al, 2018)
Functional connectivity pattern of default mode network (DMN) modulated by the risk of ATP-binding cassette A7 (ABCA7) was distributed in the right precuneus, while no significant difference was found after Gaussian random field (GRF) correction (Figure 1B)
apolipoprotein ε4 (APOEε4) might be interacted with ABCA7 and CLU modulation in the middle-aged carriers
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease with complex genetic characteristics (Lane et al, 2018). According to the findings of some genetic research, apolipoprotein ε4 (APOEε4) has been considered as the major high risk genes for AD (Rajabli et al, 2018). CLU and ABCA7 are listed as the top high risk genes secondary to APOEε4 (Corneveaux et al, 2010; Nelson et al, 2017) and both have the similar roles in lipid metabolism, immune response and clearance of Aβ aggregation (Harold et al, 2009; Tan et al, 2016). It was found that the CLU and ApoE risk variants had combined effects on both volumetric expansion and lateral ventricle enlargement in the elderly (Yu et al, 2010; Roussotte et al, 2014). It is important to study the combined effects of CLU and ABCA7 on brain to explore the underlying common pathophysiologic mechanism of AD
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