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APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

Molecular Psychiatry volume 19, pages 351–357 (2014)Cite this article

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Abstract

Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10−14) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10−8) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

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Acknowledgements

Data collection and sharing for this project was supported by the ADNI National Institutes of Health (NIH) grant U01 AG024904 (PI: Michael W Weiner, MD, VA Medical Center and University of California, San Francisco, CA, USA). Funding sources for ADNI include the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, the US Food and Drug Administration, the non-profit partners of the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation and the Dana Foundation, and the following private sector contributors: Abbott, AstraZeneca AB, Amorfix, Bayer Schering Pharma AG, Bioclinica Inc, Biogen Idec, Bristol–Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Innogenetics, IXICO, Janssen Alzheimer Immunotherapy, Johnson and Johnson, Eli Lilly and Co, Medpace Inc, Merck and Co, Inc, Meso Scale Diagnostic & LLC, Novartis AG, Pfizer Inc, F Hoffman–La Roche, Servier, Synarc, Inc and Takeda Pharmaceuticals. Private sector contributions to ADNI are facilitated by the Foundation for the NIH (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education. The study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego, CA, USA and ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Los Angeles, CA, USA. Additional ADNI support comes from the NIH grants P30 AG010129, K01 AG030514 and U24 AG21886. Data management and the specific analyses reported here were supported by NSF IIS-1117335 and NIH R01 AG19771, P30 AG10133, R01 LM011360, K24 AG027841, K99 LM011384.

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Author notes

  1. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.ucla.edu). As such, the investigators within 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.

Authors and Affiliations

  1. Department of Radiology and Imaging Sciences and Indiana Alzheimer’s Disease Center, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA

    V K Ramanan, S L Risacher, K Nho, S Kim, S Swaminathan, L Shen, T M Foroud & A J Saykin

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    V K Ramanan, S Swaminathan, T M Foroud & A J Saykin

  3. Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA

    V K Ramanan

  4. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA

    S Kim, L Shen, T M Foroud & A J Saykin

  5. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    H Hakonarson

  6. The Translational Genomics Institute (TGen), Phoenix, AZ, USA

    M J Huentelman

  7. Department of Neuroscience, University of California, San Diego, CA, USA

    P S Aisen

  8. Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA

    R C Petersen

  9. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    R C Green

  10. Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA

    C R Jack

  11. Department of Radiology, University of Michigan, Ann Arbor, MI, USA

    R A Koeppe

  12. Department of Neurology, University of California, Berkeley, CA, USA

    W J Jagust

  13. Departments of Radiology, Medicine, and Psychiatry, University of California, San Francisco, CA, USA

    M W Weiner

  14. Department of Veterans Affairs Medical Center, San Francisco, CA, USA

    M W Weiner

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Competing interests

Dr Jagust has served as a consultant to TauRx Therapeutics Ltd, GE Healthcare, Siemens, Synarc and Janssen Alzheimer Immunotherapy. Dr Weiner has served on scientific advisory boards for Eli Lilly, Araclon, Institut Catala de Neurociencies Aplicades, the Gulf War Veterans Illnesses Advisory Committee, Biogen Idec and Pfizer; has served as a consultant to Astra Zeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics Ltd, Bayer Healthcare, Biogen Idec, Exonhit Therapeutics, Servier, Synarc, Janssen, Harvard University and KLJ Associates; has received funding for travel from NeuroVigil Inc, CHRU Hôpital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Eli Lilly, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer’s Disease, the AD/PD Meeting, Paul Sabatier University, Novartis, Tohoku University, Fundacio ACE and Travel eDreams, Inc; has received honoraria from NeuroVigil, Inc, Institut Catala de Neurociencies Aplicades, PMDA/Japanese Ministry of Health, Labor and Welfare, Tohoku University and the Alzheimer’s Drug Discovery Foundation; has received research support from Merck and Avid; and has stock options for Synarc and Elan. Dr Saykin has received investigator-initiated research funding from Welch Allyn and Siemens Healthcare, and has served as a consultant or advisory board member for Siemens Healthcare and Eli Lilly. The other authors declare no conflict of interest.

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Ramanan, V., Risacher, S., Nho, K. et al. APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study. Mol Psychiatry 19, 351–357 (2014). https://doi.org/10.1038/mp.2013.19

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