APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42

• Published in: The Journal of neuroscience 2010-12, Vol.30 (50), p.17035-17040
• Main Authors: Sheline, Yvette I, Morris, John C, Snyder, Abraham Z, Price, Joseph L, Yan, Zhizi, D'Angelo, Gina, Liu, Collin, Dixit, Sachin, Benzinger, Tammie, Fagan, Anne, Goate, Alison, Mintun, Mark A
• Format: Article
• Language: English
• Subjects: Alleles; Amyloid beta-Peptides - cerebrospinal fluid; Aniline Compounds; Apolipoprotein E4 - genetics; Apolipoprotein E4 - physiology; Brain Mapping - methods; Female; Genotype; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways - diagnostic imaging; Neural Pathways - physiology; Peptide Fragments - cerebrospinal fluid; Plaque, Amyloid - metabolism; Positron-Emission Tomography - methods; Thiazoles
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.3987-10.2010

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.