title: Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.
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).
  
  
  RESULTS
  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.
authors.affiliation: Research Department P, Aarhus University Hospital, Risskov, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Søren D
authors.initials: SD
authors.lastname: Østergaard
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Lotta
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Felix
authors.initials: F
authors.lastname: Day
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Boehme
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Stefan
authors.initials: S
authors.lastname: Walter
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: John S
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Gibbons
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Seattle, Washington, United States of America.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors