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PLoS Med. 2015 Jun 16;12(6):e1001841; discussion e1001841. doi: 10.1371/journal.pmed.1001841. eCollection 2015 Jun.

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

Collaborators (296)

Albert MS, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barber RC, Barmada MM, Barnes LL, Beach TG, Becker JT, Beecham GW, Beekly D, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buxbaum JD, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cribbs DH, Crocco EA, Cruchaga C, De Jager PL, DeCarli C, Demirci F, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Evans D, Faber KM, Fallon KB, Farlow MR, Farrer LA, Ferris S, Foroud TM, Frosch MP, Galasko DR, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Goate AM, Graff-Radford NR, Green RC, Growdon JH, Haines JL, Hakonarson H, Hamilton RL, Hamilton-Nelson KL, Hardy J, Harrell LE, Head E, Honig LS, Huebinger RM, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Jun G, Kamboh M, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, Kukull WA, Kunkle BW, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lin CF, Lopez OL, Lunetta KL, Lyketsos CG, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, Mayeux R, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Murrell JR, Myers AJ, Naj AC, Olichney JM, Pankratz VS, Parisi JE, Partch A, Paulson HL, Pericak-Vance MA, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Sano M, Schellenberg GD, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, St George-Hyslop P, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, Valladares O, VanDeerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Wang LS, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L, Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Chapman J, Russo G, Hamshere M, Pahwa JS, Escott-Price V, Badarinarayan N, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan A, Taylor S, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown K, Passmore P, Craig D, McGuinness B, Todd S, Johnston J, Holmes C, Mann D, Smith A, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Heun R, Schürmann B, Ramirez A, Becker T, Herold C, Lacour A, Drichel D, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate A, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz V, Younkin SG, Holmans P, ODonovan M, Owen MJ, Williams J, Langenberg C, Scott RA, Sharp SJ, Forouhi NG, Kerrison ND, Sims M, Lucarelli DM, Barroso I, Deloukas P, McCarthy MI, Arriola L, Balkau B, Barricarte A, Boeing H, Franks PW, Gonzalez C, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós J, Rolandsson O, Sacerdote C, Sánchez MJ, Slimani N, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, Riboli E, Wareham NJ.

Author information

1
Research Department P, Aarhus University Hospital, Risskov, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
2
Department of Medicine, University of Washington, Seattle, Washington, United States of America.
3
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
4
Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
5
Department of Biology, Brigham Young University, Provo, Utah, United States of America.
6
Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
7
Department of Medicine, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Seattle, Washington, United States of America.

Abstract

BACKGROUND:

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).

METHODS AND FINDINGS:

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.

CONCLUSIONS:

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.

PMID:
26079503
PMCID:
PMC4469461
DOI:
10.1371/journal.pmed.1001841
[Indexed for MEDLINE]
Free PMC Article

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