title: APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42.
abstract: Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-β (Aβ) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aβ plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.
authors.affiliation: Department of Psychiatry, The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA. yvette@npg.wustl.edu
authors.forename: Yvette I
authors.initials: YI
authors.lastname: Sheline
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Abraham Z
authors.initials: AZ
authors.lastname: Snyder
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Price
authors.forename: Zhizi
authors.initials: Z
authors.lastname: Yan
authors.forename: Gina
authors.initials: G
authors.lastname: D'Angelo
authors.forename: Collin
authors.initials: C
authors.lastname: Liu
authors.forename: Sachin
authors.initials: S
authors.lastname: Dixit
authors.forename: Tammie
authors.initials: T
authors.lastname: Benzinger
authors.forename: Anne
authors.initials: A
authors.lastname: Fagan
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Mark A
authors.initials: MA
authors.lastname: Mintun
mesh_terms: D000483:Alleles; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds; D053327:Apolipoprotein E4 / Q000235:genetics / Q000502:physiology*; D001931:Brain Mapping / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000000981:diagnostic imaging* / Q000502:physiology*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D058225:Plaque, Amyloid / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D053327:Apolipoprotein E4; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42)