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Abstract

Objective:

To comprehensively assess neurobiological effects of the protective APOE2 allele in the aged brain using a cross-sectional multimodal neuroimaging approach.

Methods:

Multimodal neuroimaging data were obtained from a total of 572 older individuals without dementia (cognitively normal and mild cognitive impairment) enrolled in the Alzheimer's Disease Neuroimaging Initiative and included assessments of regional amyloid load with AV45-PET, glucose metabolism with fluorodeoxyglucose-PET, and gray matter volume with structural MRI. Imaging indexes of APOE2 carriers were contrasted to risk-neutral APOE3 homozygotes, and analyses were controlled for age, sex, education, and clinical diagnosis. Additional models examined genotype-specific effects of age on the imaging markers.

Results:

In region-of-interest–based analyses, APOE2 carriers had significantly less precuneal amyloid pathology and did not show the typical age-related increase in amyloid load, although the age × genotype interaction was only trend-level significant. In contrast, parietal metabolism and hippocampal volume did not differ between APOE2 and APOE3 genotypes, and both groups showed comparable negative effects of age on these markers. The amyloid specificity of APOE2-related brain changes was corroborated in 2 complementary analyses: spatially unbiased voxel-wise analyses showing widespread reductions in amyloid deposition but no differences in gray matter volume or metabolism and an analysis of CSF-based biomarkers showing a significant effect on amyloid but not on tau pathology.

Conclusions:

Regarding the range of Alzheimer disease biomarkers considered in the present study, the APOE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology in the aged brain.

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Supplementary Material

File (appendix_e-1.pdf)
File (appendix_e-2.pdf)
File (appendix_e-3.pdf)
File (coinvestigators.pdf)

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Information & Authors

Information

Published In

Neurology®
Volume 88Number 6February 7, 2017
Pages: 569-576
PubMed: 28062720

Publication History

Received: April 30, 2016
Accepted: November 16, 2016
Published online: January 6, 2017
Published in print: February 7, 2017

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Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Study Funding

Data collection and sharing for this project were funded by the ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (award no. W81XWH-12-2-0012). The ADNI was launched in 2003 by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Food and Drug Administration, private pharmaceutical companies, and nonprofit organizations as a $60 million, 5-year public-private partnership. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Co; CereSpir, Inc; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Co; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corp; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Co; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuroimaging at the University of Southern California.

Authors

Affiliations & Disclosures

Michel J. Grothe, PhD
From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité–Universitätsmedizin Berlin, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Sylvia Villeneuve, PhD
From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité–Universitätsmedizin Berlin, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Canadian Institutes of Health Research, post-doctoral fellowship, 02/12 to 01/15
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Martin Dyrba, PhD
From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité–Universitätsmedizin Berlin, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
(1) German Center for Neurodegenerative Diseases (DZNE), researcher/postdoc, six years
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
David Bartrés-Faz, PhD
From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité–Universitätsmedizin Berlin, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Spanish Ministerio de Ciencia e Innovaci?n (PSI2012-38257) research grant.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Miranka Wirth, PhD
From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité–Universitätsmedizin Berlin, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
For the Alzheimer's Disease Neuroimaging Initiative
From the German Center for Neurodegenerative Diseases (M.J.G., M.D.), Rostock, Germany; Douglas Mental Health University Institute (S.V.), Research Centre, Verdun; Department of Psychiatry (S.V.), McGill University, Montreal, Quebec, Canada; Department of Medicine (D.B.-F.), Faculty of Medicine and Health Sciences, University of Barcelona, Spain; and NeuroCure Clinical Research Center (M.W.) and Department of Neurology, Charité–Universitätsmedizin Berlin, Germany.

Notes

Correspondence to Dr. Grothe: [email protected]
Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.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 in the coinvestigators list at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Author Contributions

Michel J. Grothe: study concept, analysis and interpretation of data, drafting/revising the manuscript for content. Sylvia Villeneuve: study concept, interpretation of data, drafting/revising the manuscript for content. Martin Dyrba: analysis of data, contribution of analytic tools. David Bartrés-Faz and Miranka Wirth: study concept, interpretation of data, drafting/revising the manuscript for content.

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