Genetic variants that predict higher systolic blood pressure (SBP) are associated with a higher probability of taking antihypertensive medication and with decreased risk of Alzheimer disease (AD), according to a study published this week in PLOS Medicine. The study, conducted by Robert Scott of the MRC Epidemiology Unit, University of Cambridge, UK, Soren Ostergaard, (Aarhus University Hospital, Risskov, Denmark) and Shubhabrata Mukherjee (University of Washington, Seattle, USA) and colleagues suggests that either higher blood pressure, or anti-hypertensive therapy, may play a protective role against the development of AD.
Epidemiological studies have identified several potential risk factors for AD, but the causative nature of these associations has not been established. Without knowledge of cause, it is unclear whether health interventions upon these risk factors can alter the risk of AD. Scott and colleagues used a "Mendelian randomization" technique to test whether certain modifiable risk factors, including blood pressure, smoking, and cholesterol levels, might play a causative role in the development of AD. In Mendelian randomization, causality is inferred from associations between genetic variants linked to a risk factor, and the outcome of interest. The use of gene variants, which are inherited randomly and fixed throughout life, mitigates the risk that an identified association is mediated by a third, confounding factor related to genetic history or lifestyle.
These findings suggest that higher blood pressure (odds ratio (OR) per-SD (15.4 mmHg) of SBP [95% CI]: 0.75[0.62-0.91]; p=3.4x10-3) is associated with lower AD risk, which may be related to the effect of greater exposure to anti-hypertensive medication. Like all Mendelian randomization studies, the reliability of these results depends on the ability of the genetic variants used in the analyses to predict blood pressure, and the assumption that these genetic variants do not affect other risk factors. Moreover, as the study included an exclusively European population, the causal association may not be valid for non-European ethnic groups. Given that hypertension is a risk factor for cardiovascular disease, the researchers do not advocate raising blood pressure as a measure to prevent AD. "However," the authors state, "since there is a strong association between higher SBP gene scores and exposure to antihypertensive treatments, there is a need to evaluate the possible protective role of some of these substances against AD, independent of their effects on blood pressure."
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Research Article
Funding: This study was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372 (contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies). The work was further supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and [Institute of Psychiatry] King's College London. SDØ is supported by a grant from the Lundbeck Foundation. PP is an Alzheimer's Society Post-Doctoral Fellow. NJW is an NIHR Senior Investigator. Funding for the EPIC-InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). ADGC funding: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, U01 AG06781, U01 HG004610, U01 HG006375; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Funding for ADNI is through the Northern California Institute for Research and Education by grants from 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., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. ACT is supported by a grant (U01 AG 06781, to Dr. Larson) from the National Institutes of Health. GERAD1 funding: Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer's Research UK (ARUK) and the Welsh Assembly Government. Cambridge University and Kings College London acknowledge support from the MRC. ARUK supported sample collections at the South West Dementia Bank and the Universities of Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N.Ireland R&D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and NIHR Queen Square Dementia Biomedical Research Unit. LASER-AD was funded by Lundbeck SA. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. We acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: SDØ has received speaking fees, consultant honoraria and travel support from Janssen-Cilag until April 2011. Furthermore, he has received travel support at one occasion in 2010 from Bristol-Myers Squibb. EBL reports grants from National Institute on Aging during the conduct of the study, and personal fees from UpToDate outside the submitted work. All other authors have nothing to disclose.
Citation: Østergaard SD, Mukherjee S, Sharp SJ, Proitsi P, Lotta LA, Day F, et al. (2015) Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study. PLoS Med 12(6): e1001841. doi:10.1371/journal.pmed.1001841
Author Affiliations:
Research Department P, Aarhus University Hospital, Risskov, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Medicine, University of Washington, Seattle, Washington, United States of America
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge
Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
Department of Biology, Brigham Young University, Provo, Utah, United States of America
Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America
Group Health Research Institute, Seattle, Washington, United States of America
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