Impact Of APOE Variants On Aging:An Analysis Based On Large-scale Brain Network In Healthy Adults

PART ?.Brain Structural Networks Alterations and Impact of APOE Variants on Aging in Healthy Adults: A Graph Theory-based Magnetic Resonance Imaging Study Objective: To explore the brain structural network changes and impact of APOE variants on aging in healthy adults using graph-based analysis.Materials and methods: We enrolled 599 healthy adults(age range 20 ~ 80 years)in this study.All subjects completed neuropsychological assessments and 533 subjects underwent diffusion tensor imaging(DTI).We got APOE genotype data of 448 cases and excluded 12 subjects with APOE ?2/4.Finally,436 subjects were divided into APOE 4-group(n = 374)and APOE 4+ group(n = 62).Graph theory was used to analyze the network topological properties of the white matter network of the two groups.The correlation between these network indicators and cognitive scores and laboratory test results was calculated.Results: The neuropsychological assessments showed that the score of digit symbol test(DST)was negatively correlated with age,while the score of number connecting test(NCT)and Stroop Color Word Test(Stroop ?,Stroop ? and Stroop ?)were positively correlated with age(all P < 0.05).The scores were no difference between APOE 4-group and APOE 4+ group.The graph theory analysis showed that the normalized clustering coefficient(?)and small-world properties(?)were negatively correlated with age in APOE 4-group;the normalized characteristic path length(?)was positively correlated with age in APOE 4+ group(all P < 0.05).The ? of APOE 4+ group was higher than APOE 4-group in age 45-80(P < 0.05).The degree centrality(Dc)of right supramarginal and nodal efficiency(Ne)of right posterior cingulate cortex were negatively correlated with age in APOE 4+ group(all P < 0.0006,corrected by Bonferroni).? was positively correlated with NCT(P < 0.05).The Ne of right posterior cingulate cortex was positively correlated with DST,while negatively correlated with NCT,Stroop?and Stroop ?(all P < 0.05).Conclusion: Brain structural networks alterations were different in APOE ?4 carriers and non-carriers on aging.? of APOE ?4 carriers increased and the Ne of right posterior cingulate cortex decreased with aging,which were associated with decreased attention/executive function and responsiveness.This suggests that the APOE ?4 allele may accelerate brain aging and is associated with attention/executive function and reactivity.PART ?.Intra-and inter-network Connectivity Alterations and Impact of APOE Variants on Aging in Healthy Adults: A Large-scale Brain Functional Network Magnetic Resonance Imaging Study Objective: To explore the intra-and inter-network connectivity changes and impact of APOE variants on aging in healthy adults using the large-scale brain functional network analysis.Materials and methods: We enrolled 599 healthy adults(age range 20 ~ 80 years)in this study.All subjects underwent neuropsychological assessments and resting-state functional magnetic resonance imaging.We got 506 cases of APOE genotype data and excluded 12 subjects with APOE ?2/4.Finally,494 subjects were divided into APOE 4-group(n = 423,male / female = 150/273)and APOE 4+ group(n = 71,male / female = 27/44).The intra-and inter-network functional connectivity of 10 classical brain networks were calculated,and linear regression analysis was performed with age.The correlation between these network indicators and cognitive scores and laboratory test results was calculated.Results: The intra-network connectivity of cingulo-opercular network(CON),default mode network(DMN),subcortical network(SUB),dorsal attention network(DAN)and salience network(SAN)were negatively correlated with age(all P < 0.05).All of them were correlated with neuropsychological assessments(all P < 0.05).Further research found that the rate of intra-network connectivity decline in CON with aging was significantly faster in female APOE 4+ group than female APOE 4-group(t = 2.110,P < 0.05).The inter-network connectivity of CON,DMN,SAN,SUB and DAN with other networks were correlated with age,and were different in APOE 4-group and APOE 4+ group(all P < 0.05).Conclusion: Brain aging is mainly manifested by decreased attention and control in healthy adults,which was regulated by various resting-state functional networks such as CON,DMN,DAN,SAN,and subcortical networks.The regulation patterns of DMN-SAN-DAN-CON were different in APOE ?4 carriers and non-carriers.This suggests that the DMN-SAN-DAN-CON network is dynamically connected and regulated by APOE ?4.In addition,the brain network aging under the control of APOE ?4 alleles had certain sex differences,and female CON network was greatly affected.This may be an imaging marker to help identify aging and AD-related cognitive dysfunction.PART ?.Impact of APOE Variants with age in Healthy Adults: A Longitudinal Study Based on Dynamic Brain Functional NetworksObjective: To explore the changes in brain network of APOE ? 4 carriers and non-carriers over time by a data-driven approach and combining static and dynamic functional connections in follow up APOE ?4 carriers and non-carriers.Materials and methods: We enrolled 26 APOE 4+ subjects(median age: 24 years;median years of education: 16 years;median follow-up interval: 32 months)and 26 APOE 4+ subjects(median age: 24 years;median years of education: 16 years;median follow-up interval: 33 months)by propensity score matching(PSM).All subjects underwent neuropsychological assessments and resting-state functional magnetic resonance imaging.We analyzed static functional connections by independent component analysis(ICA),and dynamic functional connections by sliding window method.Results: There were no differences between the APOE 4-group and APOE 4+ group in general information and neuropsychological scale at baseline and follow-up levels.There was also no significant difference in general information and neuropsychological scale between baseline and follow-up for the two groups.The result of ICA showed that the functionally connected brain regions in the network were all located in the DMN network.The result of the gene main effect was on the left posterior cingulate cortex,and the result of time main effect were in the bilateral precuneus(all corrected by GRF,voxel level P <0.001,cluster level P <0.05).Dynamic functional connectivity(d FNC)found that with the growth of age,the d FNC was different in APOE ?4 carriers and non-carriers.The brain network changes of APOE ?4 non-carriers were diversity,while APOE ?4 carriers tended to change less state and have a single elevated pattern.(all corrected by FDR,P <0.05).Conclusion: This study found that APOE gene variants affected both static and dynamic functional connections in the brain network with ageing.Compared with non-carriers,APOE ?4 carriers have significantly different patterns of changes in brain network static and dynamic functional connections,which may explain the hypothesis that APOE ?4 accelerates biological aging and AD susceptibility.