title: Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease.
abstract: The apolipoprotein E (APOE) ϵ4 allele is a confirmed genetic risk factor and the APOE ϵ2 allele is a protective factor related to late-onset Alzheimer's disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between APOE ϵ2 and ϵ4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 ϵ2 carriers, 44 ϵ3 homozygotes, and 49 ϵ4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the APOE ϵ2 and ϵ4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both ϵ2 and ϵ4 carriers showed decreased functional connectivity (FC) compared with ϵ3 homozygotes, they have opposite aging trajectories in the default mode network-primarily in the bilateral anterior cingulate cortex. As age increased, ϵ2 carriers showed elevated FC, whereas ϵ4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both ϵ2 and ϵ4 carriers. It is suggested that the opposite aging trajectories between APOE ϵ2 and ϵ4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.
authors.affiliation: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.|Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Shu
authors.affiliation: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors.forename: Duan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors.forename: Chunxian
authors.initials: C
authors.lastname: Yue
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Ward
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qihao
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Brain Center, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Shi-Jiang
authors.initials: SJ
authors.lastname: Li
authors.affiliation: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000368:Aged; D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics*; D053329:Apolipoprotein E2 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000502:physiology*; D001931:Brain Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D006179:Gyrus Cinguli / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D009483:Neuropsychological Tests
chemical_list: D053329:Apolipoprotein E2; D053327:Apolipoprotein E4
keywords: aging; apolipoprotein E; functional connectivity; imaging genetics; resting-state fMRI