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Original Research ARTICLE

Front. Aging Neurosci., 01 April 2013 | http://dx.doi.org/10.3389/fnagi.2013.00011

The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI)

Shannon L. Risacher1, Sungeun Kim1,2, Li Shen1,2, Kwangsik Nho1, Tatiana Foroud3, Robert C. Green4, Ronald C. Petersen5, Clifford R. Jack Jr.6, Paul S. Aisen7, Robert A. Koeppe8, William J. Jagust9, Leslie M. Shaw10, John Q. Trojanowski10, Michael W. Weiner11,12, Andrew J. Saykin, for the Alzheimer's Disease Neuroimaging Initiative (ADNI)
  • 1Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA
  • 2Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA
  • 3Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
  • 4Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  • 5Department of Neurology, Mayo Clinic, Rochester, MN, USA
  • 6Department of Radiology, Mayo Clinic, Rochester, MN, USA
  • 7Department of Neurology, University of California, San Diego, San Diego, CA, USA
  • 8Department of Radiology, University of Michigan, Ann Arbor, MI, USA
  • 9Department of Neurology, University of California, Berkeley, Berkeley, CA, USA
  • 10Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  • 11Departments of Radiology, Medicine, and Psychiatry, University of California, San Francisco, San Francisco, CA, USA
  • 12Department of Veterans Affairs Medical Center, San Francisco, CA, USA
  • Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort.

Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints.

Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed.

Conclusions: APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.

Keywords: apolipoprotein E (APOE), early mild cognitive impairment (E-MCI), Florbetapir/AV-45/Amyvid, positron emission tomography (PET), magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), Alzheimer's disease neuroimaging initiative (ADNI)

Citation: Risacher SL, Kim S, Shen L, Nho K, Foroud T, Green RC, Petersen RC, Jack Jr. CR, Aisen PS, Koeppe RA, Jagust WJ, Shaw LM, Trojanowski JQ, Weiner MW and Saykin AJ (2013) The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI). Front. Aging Neurosci. 5:11. doi: 10.3389/fnagi.2013.00011

Received: 19 December 2012; Paper pending published: 17 January 2013;
Accepted: 01 March 2013; Published online: 01 April 2013.

Edited by:

Manuel Menéndez-González, Hospital Álvarez-Buylla, Spain

Reviewed by:

Gregory A. Jicha, University of Kentucky, USA
Maria S. M. Palomo, Centro de Especialidades de la Avenida de Portugal y guardias de Neurología, Spain
Marwan N. Sabbagh, Banner Sun Health Research Institute, USA

Copyright © 2013 Risacher, Kim, Shen, Nho, Foroud, Green, Petersen, Jack, Aisen, Koeppe, Jagust, Shaw, Trojanowski, Weiner and Saykin. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License,new, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Andrew J. Saykin, Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, IU Health Neuroscience Center, Suite 4100, 355 West 16th Street, Indianapolis, IN 46202, USA. e-mail: asaykin@iupui.edu.