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CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner

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Abstract

Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer’s disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.

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Acknowledgements

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., and Wyeth, as well as non-profit partners the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.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 Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation.

J.B.B. is supported by NINDS K02 NS067427, NIA U01 AG10483, NIA P50 AG005131, NIA RC2AG036535 and General Electric Medical Foundation and is an investigator for, and receives research funds from Janssen Alzheimer Immunotherapy. He has served on advisory boards for Elan and Avanir Pharmaceuticals, holds stock options in CorTechs Labs, Inc., and serves as an editor for the International Journal of Alzheimer’s Disease; E.A.M. is supported in part by NIGMS Training Grant GM007198.

A.M.D. receives funding to his laboratory from General Electric Medical Systems as part of a Master Research Agreement with UCSD; and is a founder of, holds equity in, and serves on the scientific advisory board for CorTechs Labs, Inc. The terms of this arrangement have been reviewed and approved by UCSD in accordance with its conflict of interest policy.

Address correspondence to J. B. Brewer, Human Memory Laboratory, 8950 Villa La Jolla Drive, C212, La Jolla, CA 92037, USA. Email: jbrewer@ucsd.edu.

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Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, CA, USA

    Elizabeth A. Murphy, Dominic Holland, Anders M. Dale & James B. Brewer

  2. Department of Radiology, University of California, San Diego, CA, USA

    Linda K. McEvoy, D. J. Hagler Jr, Anders M. Dale & James B. Brewer

  3. Multimodal Imaging Laboratory, University of California, San Diego, CA, USA

    John Cooper Roddey, Linda K. McEvoy, Dominic Holland, D. J. Hagler Jr & Anders M. Dale

  4. Human Memory Laboratory, 8950 Villa La Jolla Drive C212, La Jolla, CA, 92037, USA

    James B. Brewer

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  1. Elizabeth A. Murphy
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Alzheimer’s Disease Neuroimaging Initiative

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Correspondence to James B. Brewer.

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Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). 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 is available at http://www.loni.ucla.edu/ADNI/Collaboration/ADNI_Manuscript_Citations.pdf.

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Murphy, E.A., Roddey, J.C., McEvoy, L.K. et al. CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner. Brain Imaging and Behavior 6, 16–26 (2012). https://doi.org/10.1007/s11682-011-9137-0

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