The Regulation Of Lipid Metabolism-related Genes On Functional Brain Networks In Individuals At Risk Of Alzheimer’s Disease

Part one: The longitudinal effects of apolipoprotein E gene on hippocampus networks in subjects with amnestic-type mild cognitive impairmentObjective: Although apolipoprotein E(Apo E)gene is the most important genetic factor for sporadic Alzheimer’s disease(AD),the mechanisms underlying the link remain relatively unknown.Aging is a well-known risk factor for AD and could strongly interact with Apo E-related vulnerabilities to affect AD risk.The present study aimed to investigate the longitudinal effects of Apo E gene on hippocampus networks in subjects with amnestic-type mild cognitive impairment(aMCI).Methods: Eighty-seven aMCI subjects and 135 matched cognitively normal(CN)elderly subjects underwent resting-state f MRI scans and neuropsychological tests at baseline and at a 35-month follow-up.Hippocampal resting-state functional connectivity(FC)data were analyzed utilizing a mixed analysis of covariance with Apo E genotype,time points and disease as fixed factors,controlling for age,sex and years of education.Results: The notable finding was that the FC between the left hippocampus and right frontal regions for Apo E ε4 carriers longitudinally increased in CN subjects,but decreased in aMCI patients,whereas the FC for non-carriers was maintained in CN subjects but increased in aMCI patients.Specifically,the longitudinal increases in hippocampal FC with the right inferior frontal gyrus were positively correlated with the changes in episodic memory test scores in non-carriers with aMCI.Conclusion: Compensatory neural processes were accelerated in Apo E ε4 carriers,but could be subsequently exhausted with the onset of cognitive impairment.Aging should be considered a key regulator of the impact of the Apo E genotype on the phenotypic variants of AD.Part two: The longitudinal trajectories of resting-state networks in individuals carrying apolipoprotein E ε4 alleleObjective: Increased FC in resting-state networks has been shown in individuals at risk of AD by many studies.However,the longitudinal trajectories of the FC remain relatively unknown.The present study aimed to explore the longitudinal changes of increased FC in multiple resting-state networks in subjects with Apo E ε4 allele or/and aMCI.Methods: Eighty-seven aMCI subjects and 135 matched CN elderly subjects underwent resting-state f MRI scans and neuropsychological tests at baseline and at a 35-month follow-up.Subjects were divided into 4 groups according to the diagnosis and Apo E status.The CN non-Apo E ε4 group served as a control group and other groups served as AD risk groups.The cross-sectional and longitudinal patterns of 4 resting-state networks,including default mode network(DMN),hippocampus network,executive control network,and salience network,were explored by comparing FC data between groups and between time points respectively.Results: At baseline,compared with the control group,AD risk groups showed increased FC with eight regions in multiple networks.At follow-up,six of the regions displayed longitudinally decreased FC in AD risk groups.In contrast,the FC with all above regions maintained in the control group.Notably,among 3 risk groups,most of the increased FC at baseline(5/8)and longitudinally decreased FC at follow-up(4/6)were shown in aMCI Apo E ε4 group.Conclusion: Increased resting-state FC is followed by a decline in subjects at AD risk and this inverse U-shaped trajectory is more notable in subjects with higher risk.Part three: Shared effects of clusterin gene on default mode network among individuals at risk for Alzheimer’s diseaseObjective: To explore the common effects of the clusterin(CLU)rs11136000 variant on the DMN in aMCI subjects and remitted geriatric depression(RGD)subjects.Methods: Eighty-seven aMCI subjects,72 RGD subjects and 135 cognitively normal elderly subjects underwent resting-state f MRI scans and neuropsychological tests at both baseline and a 35-month follow-up.The posterior cingulate cortex seed-based FC analysis was used to obtain the DMN patterns.Results: The CLU gene × disease × time interaction for aMCI subjects was mainly detected n the core cortical midline structures of the DMN,and the interaction for RGD subjects was mainly detected in the limbic system.However,they overlapped in 2 frontal regions,where consistent effects of the CLU gene on FC alterations were shown between aMCI and RGD groups.Furthermore,the alterations of FC with frontal,parietal and limbic regions compensated for episodic memory impairments in CLU-CT/TT carriers,while no such compensation was found in CLU-CC carriers.Conclusion: The CLU gene could consistently affect the DMN FC with frontal regions among individuals at risk for Alzheimer’s disease,and the CLU-T allele was associated with more compensatory neural processes in DMN changes.