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Interaction of insulin and PPAR-α genes in Alzheimer’s disease: the Epistasis Project

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Abstract

Altered glucose metabolism has been described in Alzheimer’s disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.

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Acknowledgments

We are most grateful to the Moulton Charitable Foundation for a grant to fund the Epistasis Project, to all those who have provided support for the individual clinical studies and to the Alzheimer’s Research Trust. GKW was partly funded by the NIHR Biomedical Research Centre Programme, Oxford.

Conflict of interest

Professor Maier received research grants from the following companies, respectively, is member of the Advisory Boards or draws a fee for speech from: AstraZeneca, Bayer Vital, Böhringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, General Electrics, Janssen-Cilag, Lundbeck, Merck, Merz, Novartis, Pfizer, Sanofi-Aventis, Schering. The other authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Psychiatry, University of Bonn, Bonn, Germany

    Heike Kölsch, Wolfgang Maier & Reinhard Heun

  2. Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK

    Donald J. Lehmann, Michael G. Lehmann, Donald R. Warden & A. David Smith

  3. Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    Carla A. Ibrahim-Verbaas & Maaike Schuur

  4. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    Carla A. Ibrahim-Verbaas, Cornelia M. van Duijn, Yurii S. Aulchenko, Maaike Schuur & Monique Breteler

  5. Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), 39008, Santander, Spain

    Onofre Combarros & Ignacio Mateo

  6. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK

    Naomi Hammond & Panos Deloukas

  7. School of Molecular Medical Sciences, Institute of Genetics, Queens Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    Olivia Belbin, Kristelle Brown & Kevin Morgan

  8. Institute of Child Health, Centre for Paediatric Epidemiology and Biostatistics, University College London, 30 Guilford Street, London, WC1N 1EH, UK

    Mario Cortina-Borja

  9. Nuffield Department of Medicine, University of Oxford, Level 4, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Gordon K. Wilcock

  10. Institute of Clinical Neurosciences, Dementia Research Group, Frenchay Hospital, University of Bristol, Frenchay, Bristol, BS16 1LE, UK

    Patrick G. Kehoe & Rachel Barber

  11. Genética Molecular, Hospital Central de Asturias, Oviedo, Spain

    Eliecer Coto & Victoria Alvarez

  12. Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3WQ, UK

    Reinhard Heun

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  1. Heike Kölsch
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  2. Donald J. Lehmann
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Correspondence to Heike Kölsch or Reinhard Heun.

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Kölsch, H., Lehmann, D.J., Ibrahim-Verbaas, C.A. et al. Interaction of insulin and PPAR-α genes in Alzheimer’s disease: the Epistasis Project. J Neural Transm 119, 473–479 (2012). https://doi.org/10.1007/s00702-011-0732-4

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