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Objective  To 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.    Methods  A 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.    Results  Compared 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.    Conclusion  The 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.

Impacts of AD-Related ABCA7 and CLU Variants on Default Mode Network Connectivity in Healthy Middle-Age Adults