title: Apolipoprotein E ε4 modulates functional brain connectome in Alzheimer's disease.
abstract: The apolipoprotein E (APOE) ɛ4 allele is a well-established genetic risk factor for Alzheimer's disease (AD). Recent research has demonstrated an APOE ɛ4-mediated modulation of intrinsic functional brain networks in cognitively normal individuals. However, it remains largely unknown whether and how APOE ɛ4 affects the brain's functional network architecture in patients with AD. Using resting-state functional MRI and graph-theory approaches, we systematically investigated the topological organization of whole-brain functional networks in 16 APOE ɛ4 carriers and 26 matched noncarriers with AD at three levels: global whole-brain, intermediate module, and regional node/connection. Neuropsychological analysis showed that the APOE ɛ4 carriers performed worse on delayed memory but better on a late item generation of a verbal fluency task (associated with executive function) than noncarriers. Whole-brain graph analyses revealed that APOE ɛ4 significantly disrupted whole-brain topological organization as characterized by (i) reduced parallel information transformation efficiency; (ii) decreased intramodular connectivity within the posterior default mode network (pDMN) and intermodular connectivity of the pDMN and executive control network (ECN) with other neuroanatomical systems; and (iii) impaired functional hubs and their rich-club connectivities that primarily involve the pDMN, ECN, and sensorimotor systems. Further simulation analysis indicated that these altered connectivity profiles of the pDMN and ECN largely accounted for the abnormal global network topology. Finally, the changes in network topology exhibited significant correlations with the patients' cognitive performances. Together, our findings suggest that the APOE genotype modulates large-scale brain networks in AD and shed new light on the gene-connectome interaction in this disease.
authors.affiliation: State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China; Center for Cognition and Brain Disorders, Hangzhou Normal University, Hangzhou, China; Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Huali
authors.initials: H
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: He
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000503:physiopathology*; D003198:Computer Simulation; D063132:Connectome; D005260:Female; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008959:Models, Neurological; D009434:Neural Pathways / Q000503:physiopathology; D009483:Neuropsychological Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D012146:Rest
chemical_list: D053327:Apolipoprotein E4
keywords: connectomics; default mode; functional connectivity; graph theory; module; resting-state fMRI