Hippocampus And Subregion Dependant Functional And Effective Connectivity Alteration Pattern In Young APOE ε4 Carriers

Background and Objective The apolipoprotein E(APOE)ε4 allele is considered as the strong genetic risk factor of Alzheimer’s disease(AD),and closely related to the alteration in functional activation,microstructure and metabolisim of healthy brain,particularly to the earliest abberance of functional connectivity pattern in the young stage.The hippocampus is one of the earliest loci affected by the accumulation of AD lesions,the abnormal functional connectivity pattern of which is always affected in subjects with AD and mild cognitive impairment,as well as healthy carriers.However,few research has been explored the hippocamous-based functional connectivity in the young APOE ε4 carriers.Since the subregions of hippocampus have been further revealed with different roles in the multiple cognitive function domains,the objective of this study was to investigate hippocampus and subregion-based functional connectivity pattern in the healthy young carriers with APOE ε4.Materials and Methods Two hundred and thirteen young healthy adults underwent resting-state functional magnetic resonance imaging at a 3T MR scanner,the neuropsychological tests and genotype testing for APOE ε3 and ε4 allele.Age-,gender-and educational level-matched individuals,including 30 subjects with APOE ε4 and 30 subjects with APOE ε3 were enrolled for the final analysis.The hippocampi(Hippo)were divided along the A-P axis into three equal sections(Hipposub 1/2/3 stands for the anterior,middle and posterior portions of the hippocampus,respectively).The hippocampus and subregion-based functional connectivity mappings were compared between the two groups.Correlation analysis was also performed between abnormal functional connectivity values and clinical indicesResults Compared with the APOE ε3 group,the APOE ε4 group showed the increased functional connectivity between Hippo(L/R)/Hipposubl/2(L/R)and medial prefrontal cortex(MPFC)and anterior cingulate cortex(ACC),as well as between Hippo(R)/Hipposubl(R)and posterior cingulate cortex(PCC),precuneus(PCu)and left calrine and lingual gyrus.Besides,the z values from Hippo(L)/Hipposub2(L)-ACC/MPFC positively correlated to the scores of vocabulary learning test.Oppositely,the z values of Hippo(R)/Hipposubl/2(R)-ACC/MPFC negatively correlated to the scores of Montreal Cognitive Assessment,and the z values of Hipposub 1(R)-ACC/MPFC showed positive correlation with self-rating depression scales.Conclusion The APOE s4 carriers displayed altered Hippo and Hipposub 1/2-based functional connectivity pattern distributed in the core regions of defaut mode network(DMN)when compared with APOE ε3 carriers.Furthermore,the right Hippo and Hipposub1-based functional connectivity alteration is more widely affected in APOEε4 carriers.The increased functional conectivtiy patterns between bilateral Hippo/Hipposubl/2 and DMN might be the genetic phenotype underlying the ealy modulated mechanism.Background and Objective Previous studies have demonstrated the hippocampus(Hippo)and subregion(sub)-based alteration in the young stage;however,the interation effect of time and APOE ε4 on functional connectivity has been uncovered.The second part of this thesis is thus to determine whether the functional and effective connectivity based on the subregions of hippocampus is altered in APOEε4 carriers in a 3-year follow-up durationMaterials and methods Resting-state functional MRI data and neuropsychological scales were obtained for APOE ε4 and APOE ε3 carriers at baseline and three-year follow-up.The Hippo-and Hipposub-based functional connectivity patterns were compared by mixed effect analysis and further post-hoc analysis.The effective connectivity patterns among the altered regions,affected by APOE ε4-by-time interaction,were examined in APOE s4 groups at baseline and follow-up.The correlation analysis was conducted between the values of altered functional connectivity or effective connectivity and neuropsychological scalesResults The APOE ε4-by-time interaction effect was evident in functional connectivity between Hipposub3(L)and left middle and superior temporal gyrus(MTG/STG),sub2(R)and MTG/STG(L),and Hipposub3(R)and anterior cingulate cortex(ACC)The Post-hoc analysis revealed decreased functional connectivity in Hipposub3(L)-MTG/STG(L);Hipposub3(R)-ACC,and increased functional connectivity in Hipposub2(R)-MTG/STG(L)in APOE ε4 group at baseline when compared with APOE ε3 group.The APOE ε4 group at follow-up showed increased functional connectivity in Hipposub3(L)-MTG/STG(L),Hipposub3(R)-ACC and decreased functional connectivity in Hipposub2(R)-MTG/STG(L).The functional connectivity in Hipposub3(L)-MTG/STG(L)at baseline and sub2(R)-MTG/STG(L)at follow-up correlated with the scores of scales both in APOE ε3 and APOE ε4 group.Besides,the APOE ε4 group showed increased effective connectivity separately from Hipposub2(L)/MTG/STG(L)to Hipposub3(L)among altered regions(the bilateral Hipposub2/3,MTG/STG(L)and ACC).The values of changes in effective connectivity from MTG/STG(L)to Hipposub3(L)positively correlated with the scores of delayed recall test.Conclusion The posterior portion of hippocampus might be most vulnerable and susceptible to early modulation of interaction of APOE ε4 by time,and the altered activtity bwtween MTG/STG and which might be used as the longitudinal imaging-derived phenotype in APOE ε4 carriers.