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Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

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Abstract

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

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Acknowledgements

We thank the Shiley-Marcos Alzheimer’s Disease Research Center at UCSD and the Memory and Aging Center at UCSF for continued support and the International Genomics of Alzheimer’s Project (IGAP) for providing summary result data for these analyses. This work was supported by Grants from the National Institutes of Health (NIH-AG046374, K01AG049152), Alzheimer’s Disease Genetics Consortium (U01 AG032984), National Alzheimer’s Coordinating Center Junior Investigator Award (RSD), RSNA Resident/Fellow Award (RSD), Foundation ASNR Alzheimer’s Imaging Grant (RSD), the Research Council of Norway (#213837, #225989, #223273, #237250/EU JPND), the South East Norway Health Authority (2013-123), Norwegian Health Association and the KG Jebsen Foundation.

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  1. Iris J. Broce and Chin Hong Tan contributed equally.

Authors and Affiliations

  1. Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA

    Iris J. Broce, Chin Hong Tan, Christopher P. Hess, William P. Dillon, Christine M. Glastonbury, Leo P. Sugrue & Rahul S. Desikan

  2. Division of Psychology, Nanyang Technological University, Singapore, Singapore

    Chin Hong Tan

  3. Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA

    Chun Chieh Fan & Anders M. Dale

  4. Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Iris Jansen, Jeanne E. Savage & Danielle Posthuma

  5. Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Aree Witoelar & Ole A. Andreassen

  6. Department of Psychiatry, Washington University in St Louis, 425 S Euclid Ave, Campus Box 8134, St Louis, MO, 63110, USA

    Natalie Wen & Celeste M. Karch

  7. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

    Maria Glymour & Kristine Yaffe

  8. Department of Neurology, University of California, San Francisco, CA, USA

    Jennifer S. Yokoyama, Fanny M. Elahi, Gil D. Rabinovici, Bruce L. Miller & Kristine Yaffe

  9. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

    Elizabeth C. Mormino

  10. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Reisa A. Sperling & Bradley T. Hyman

  11. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Reisa A. Sperling

  12. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    David A. Bennett

  13. Department of Radiology, University of California, San Diego, La Jolla, CA, USA

    Linda K. McEvoy, James B. Brewer & Anders M. Dale

  14. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    James B. Brewer, Howard H. Feldman & Anders M. Dale

  15. Shiley-Marcos Alzheimer’s Disease Research Center, University of California, La Jolla, San Diego, CA, USA

    James B. Brewer

  16. John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA

    Margaret Pericak-Vance

  17. Department of Epidemiology and Biostatistics, Case Western University, Cleveland, OH, USA

    Jonathan L. Haines

  18. Institute for Computational Biology, Case Western University, Cleveland, OH, USA

    Jonathan L. Haines

  19. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    Lindsay A. Farrer

  20. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Lindsay A. Farrer

  21. Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA

    Lindsay A. Farrer

  22. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Lindsay A. Farrer

  23. Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

    Lindsay A. Farrer

  24. Department of Neurology, Columbia University, New York, NY, USA

    Richard Mayeux

  25. Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

    Richard Mayeux

  26. Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA

    Richard Mayeux

  27. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Gerard D. Schellenberg

  28. Department of Psychiatry, University of California, San Francisco, CA, USA

    Kristine Yaffe

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Correspondence to Iris J. Broce, Celeste M. Karch or Rahul S. Desikan.

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Conflict of interest

JBB served on advisory boards for Elan, Bristol-Myers Squibb, Avanir, Novartis, Genentech, and Eli Lilly and holds stock options in CorTechs Labs, Inc. and Human Longevity, Inc. AMD is a founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

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Broce, I.J., Tan, C.H., Fan, C.C. et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. Acta Neuropathol 137, 209–226 (2019). https://doi.org/10.1007/s00401-018-1928-6

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  • DOI: https://doi.org/10.1007/s00401-018-1928-6

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