Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

Søren D. Østergaard, Shubhabrata Mukherjee, Stephen J. Sharp, Petroula Proitsi, Luca A. Lotta, Felix Day, John R.B. Perry, Kevin L. Boehme, Stefan Walter, John S. Kauwe, Laura E. Gibbons, Eric B. Larson, John F. Powell, Claudia Langenberg, Paul K. Crane, Nicholas J. Wareham, Robert A. Scott, Marilyn S. Albert, Roger L. Albin, Liana G. ApostolovaSteven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Robert C. Barber, Michael M. Barmada, Lisa L. Barnes, Thomas G. Beach, James T. Becker, Gary W. Beecham, Duane Beekly, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, David H. Cribbs, Elizabeth A. Crocco, Carlos Cruchaga, Philip L. De Jager, Charles DeCarli, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Ranjan Duara, Nilufer Ertekin-Taner, Denis Evans, Kelley M. Faber, Kenneth B. Fallon, Martin R. Farlow, Lindsay A. Farrer, Steven Ferris, Tatiana M. Foroud, Matthew P. Frosch, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Jonathan D. Glass, Alison M. Goate, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Jonathan L. Haines, Hakon Hakonarson, Ronald L. Hamilton, Kara L. Hamilton-Nelson, John Hardy, Lindy E. Harrell, Elizabeth Head, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee Way Jin, Gyungah Jun, M. Ilyas Kamboh, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Neil W. Kowall, Joel H. Kramer, Walter A. Kukull, Brian W. Kunkle, Frank M. LaFerla, James J. Lah, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Chiao Feng Lin, Oscar L. Lopez, Kathryn L. Lunetta, Constantine G. Lyketsos, Wendy J. Mack, Daniel C. Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Richard Mayeux, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Jill R. Murrell, Amanda J. Myers, Adam C. Naj, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Amanda Partch, Henry L. Paulson, Margaret A. Pericak-Vance, William Perry, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Mark A. Sager, Mary Sano, Gerard D. Schellenberg, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A. Stern, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Otto Valladares, Vivianna M. VanDeerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Li San Wang, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Sarah Wishnek, Randall L. Woltjer, Clinton B. Wright, Steven G. Younkin, Chang En Yu, Lei Yu, Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Jade Chapman, Giancarlo Russo, Marian Hamshere, Jaspreet Singh Pahwa, Valentina Escott-Price, Nandini Badarinarayan, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad Morgan, Sarah Taylor, Simon Lovestone, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle Brown, Peter Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Janet Johnston, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Reiner Heun, Britta Schürmann, Alfredo Ramirez, Tim Becker, Christine Herold, André Lacour, Dmitriy Drichel, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison Goate, John S.K. Kauwe, Petra Nowotny, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E. Shaw, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl Heinz Jöckel, Norman Klopp, H. Erich Wichmann, V. Shane Pankratz, Peter Holmans, Michael O. Donovan, Michael J. Owen, Julie Williams, Nita G. Forouhi, Nicola D. Kerrison, Matt Sims, Debora M.E. Lucarelli, Inês Barroso, Mark I. McCarthy, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Heiner Boeing, Paul W. Franks, Carlos Gonzalez, Sara Grioni, Rudolf Kaaks, Timothy J. Key, Carmen Navarro, Peter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J. Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, Maria José Sánchez, Nadia Slimani, Anne Tjonneland, Rosario Tumino, A. L. van der Daphne, Yvonne T. van der Schouw, Elio Riboli

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143 Scopus citations

Abstract

Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs= 49), fasting glucose (NSNPs= 36), insulin resistance (NSNPs= 10), body mass index (BMI, NSNPs= 32), total cholesterol (NSNPs= 73), HDL-cholesterol (NSNPs= 71), LDL-cholesterol (NSNPs= 57), triglycerides (NSNPs= 39), systolic blood pressure (SBP, NSNPs= 24), smoking initiation (NSNPs= 1), smoking quantity (NSNPs= 3), university completion (NSNPs= 2), and years of education (NSNPs= 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10−3). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10−8). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10−3), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk.

Original languageEnglish
Article numbere1001841
JournalPLoS Medicine
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Østergaard et al.

ASJC Scopus subject areas

  • General Medicine

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