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HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study

Molecular Psychiatry volume 20, pages 867–873 (2015)Cite this article

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Abstract

Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer’s disease Cooperative study (ADCS) and Alzheimer’s disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G−) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR’s G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.

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Acknowledgements

This study was supported in part by the Natural Sciences and Engineering Research Council of Canada (JP), JL Levesque Foundation (JP) and by the Canadian Institutes of Health Research (VL/LDB/JP). We would also like to thank Mrs Danielle Cécyre at the Douglas Institute/ Bell Canada Brain Bank for providing human brain tissues. 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, Biogen Idec, Bristol–Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Innogenetics, IXICO, Janssen Alzheimer Immunotherapy, Johnson and Johnson, Eli Lilly, Medpace, Merck, Meso Scale Diagnostic & LLC, Novartis AG, Pfizer, F Hoffman–La Roche, Servier, Synarc 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. We also wish to thank all the members and funders of the ADCS who participated in the original MCI study.

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  1. Members of the Alzheimer's Disease Neuroimaging Initiative are listed before the references.

Authors and Affiliations

  1. Centre for the Studies in the Prevention of Alzheimer’s disease, Douglas Mental Health University Institute, Montreal, QC, Canada,

    V Leduc, L De Beaumont, L Théroux, D Dea & J Poirier

  2. Department of Nutrition, Institut de recherches cliniques de Montréal, Université de Montréal, Montreal, QC, Canada,

    V Leduc & R Dufour

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

    P Aisen

  4. Alzheimer's Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA,

    R C Petersen

  5. Derparment of Psychiatry, McGill University, Verdun, QC, Canada,

    J Poirier

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Leduc, V., De Beaumont, L., Théroux, L. et al. HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study. Mol Psychiatry 20, 867–873 (2015). https://doi.org/10.1038/mp.2014.81

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