Impacts Of ABCA7 And CLU Variants Associated With Alzheimer’s Disease On The Function Connectivity Of Dmn In Healthy Middle-age Adults

Background and Objective Alzheimer’s disease(AD)is a neurodegenerative disease with multiple genetic phenotypes and complex genetic characteristics.Clusterin(CLU)is the largest lipoprotein in the brain second only to Apolipoprotein E(APOE),asl well as play the similar biological function.ATP binding cassette A7(ABCA7),as a member of ABC transporter superfamily,was top ten AD risk genes together with CLU.The default mode network(DMN)is one of the most vulnerable target during the occurrence and development of AD.The purpose of this study is to investigate the risk of ABC A7 and CLU on the function connectivity of DMN in healthy middle-age adults.Materials and Methods We performed resting-state functional MR examinations and neuropsychological scales on 147 healthy middle-aged volunteers.Peripheral venous blood was collected for genotyping of CLU and ABCA7.A single nucleotide polymorphism detection technique was used to genotype four sites of the CLU gene and two sites of the ABCA7 gene.The genotypes were integrated according to the degree of risk as followed.The homozygote with the dangerous genotype was scored as 2 points,the heterozygote was scored as 1 point,and the homozygote without risk gene was scored as 0 point.With the median as the boundary,the CLU and ABC A7 risk scores were further divided into groups,with CLU(0,1,and 2 points)as the low-risk group and CLU(3,4,5,and 6)as the high-risk group.Similarly,ABCA7(0,1 points)was considered as low-risk group and ABCA7(2,3,4,5,6 points)was considered as high-risk group.Later,we constructed the function connectivity of DMN by posterior cingulate cortex(PCC)-based functional connectivity.An independent two-sample t-test was used to compare the function connectivity of DMN betwee high-and low-risk groups.Correlation analysis was compaered with z-values of the brain with significant differences and the neuropsychology scale.Results For the analysis of 147 subjects,there was no significant difference between the risk degree of the total risk gene scores and both age and the neuropsychological scale(P>0.05).The correlation analysis between risk degree of the total risk gene scores in CLU and DMN showed that the major differences between high-risk and low-risk group were located in the left middle frontal cortex(GRF corrected,P<0.05).As for ABCA7,the major differences between high-risk and low-risk group were located in the right precuneus,while there was no significant difference between the two groups After GRF correction.Conclusion The major differences between high-risk and low-risk group,divided from CLU genotype scores,were located in the left medial prefrontal cortex,suggesting that there was a regulation of CLU in healthy middle-age adults.Background and Objective The APOE e4 is a well-recognized gene with the highest risk for Alzheimer’s disease(AD).The alteration of brain function connection in APOEε4 carriers is earlier than that of brain structure or blood flow changes.Both CLU and ABCA7 are similarly involved in lipid metabolism,immune response and clearance of Aβ aggregation with the common pathophysiology of AD.This study was thus to investigate the effects of ABCA7 and CLU gene polymorphisms on the function connectivity of DMN in healthy middle-aged adults.Materials and Methods We performed resting-state functional MR examinations and neuropsychological scales on 147 healthy middle-aged volunteers.Peripheral venous blood was collected for genotyping of CLU and ABCA7.The variants of rs9331888 were genotyped as CC,GC,and GG,and subjects with-G genotype(GG+GC)were divided as high risk group according to the AD-related mutation gene;Similarly,The variants of ABCA7 rs3764650 were genotyped as GG,GT,and TT,and-G genotype group(GG+GT)was consider as dangerous group.According to different combinations of two gene variants,All the subjects were divided into three groups:high-risk group,middle-risk group and low-risk group.Middle-risk group was further divided into CLU-prodominant middle-risk group and ABCA7-prodominant middle-risk group.ANOVA analysis was used to compare the differences in PCC-based functional connectivity among the different groups.In order to exclude the effect of APOEs4 on the genetic variants of CLU and ABCA7,all subjects with APOEs were excluded from the study and the ANOVA were re-analyzed in three and four group.Finally,a bivariate correlation analysis was computed beteween z-values of the brain with significant differences and neuropsychology scale.Results For the analysis of 147 subjects,there was no significant difference beetween the risk degree of the total risk gene scores and age and the neuropsychological scale among the three groups(low-risk group,midle-risk group,high-risk group)and the four groups(low-risk group,CLU-prodominant middle-risk group,ABCA7-prodominant middle-risk group,high-risk group)(P>0.05).With the inclusion of subjects with APOEs4,the major differences of function connectivity of DIVMN among the three groups were distributed in the bilateral medial prefrontal cortex(MPC)and bilateral superior frontal gyrus(SFG).When compared with the low-and high-risk group,middle-risk group displayed the lower functional connectivity in MPC/SFG(GRF corrected,P<0.05).Similarly,the differences resulted from ANOVA with four groups were located in the bilateral MPC(GRF corrected,P<0.05),while the low-risk group displayed the increased functional connectivity in MPC only when compared with CLU-prodominant middle-risk group(GRF corrected,P<0.05).When APOEe4 carriers were excluded,the major differences among the three groups were located in the MPC/SFG,andGRF the low-risk group displayed the enhanced activity in MPC/SFG when compared with middle-riske group(GRF corrected,P<0.05).Interesting,ANOVA resulted from four groups demonstrated the altered activity in MPC and cuneus.Specifically,GRFthe low-risk group showed enhanced functional connecticity in MPC when compared with CLU-prodominant middle-risk group,while the high-risk group displayed increased activity in cuneus when compared with ABCA7-prodominant middle-risk group(GRF corrected,P<0.05).GRF Additionally,the z values of MPC and cuneus distracted from the result of ANOVA were similarly positively related to the scores of MoCA(P<0.05).Conclusion APOε4 may be involved in the regulation of CLU and ABCA7 gene viriants so as to affect the function activity of DMN.MPC was modulate by the interaciton of CLU and ABCA7 without APOE4 effect,which suggested that the MFC was the common target brain region of abnormal lipid metabolism under the regulation of different genes in the pathogenesis of AD.Moreover,the genetic effect of CLU might be interacted with ABCA7 modulation in the middle-aged carriers.