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 language | English |
|---|---|
| Article number | e1001841 |
| Journal | PLoS Medicine |
| Volume | 12 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2015 |
Bibliographical note
Publisher Copyright:© 2015 Østergaard et al.
Funding
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.
| Funders | Funder number |
|---|---|
| European Commission | |
| National Institute on Aging | P50AG005144, R01AG033193, P50AG005146, RC2AG036535, P50AG005142, R01AG035137, U24AG021886, U01AG024904, R01AG019085, R01AG025259, U01AG016976, P01AG010491, R01AG013616, RC2AG036528, P50AG005133, R01AG012101, P50AG005134, P50AG005131, K01AG030514, P30AG013854, P30AG028383, R01AG027944, P50AG016582, U01AG010483, P50AG005136, R01AG022374, P50AG025688, P50AG005138, P50AG023501, R01AG041232, R01AG011101, R01AG021547, P50AG005681, P50AG008671, P30AG028377, R37AG015473, R01AG041718, R01AG026916, R01AG030146, P01AG019724, U01AG006781, P50AG016573, P50AG016574, P30AG010133, P30AG013846, R01AG030653, P50AG016570, R01AG017917, P01AG002219, R01AG015819, U01AG032984, R01AG042611, RC2AG036502, R01AG019757, R01AG026390, R01AG020688, R01AG017173, R01AG031581, P30AG008017, U24AG026395, P30AG012300, P30AG010161, P01AG003991, P30AG010129, P30AG019610, P30AG008051, P50AG008702 |
| Seventh Framework Programme | 115372 |
| National Human Genome Research Institute | U01HG008657, U01HG006375, U01HG004610 |
| UK Medical Research Council, Engineering and Physical Sciences Research Council | MC_UU_12015/1, G0300429, MC_PC_13048, MR/L023784/1, MR/K006584/1, MR/L010305/1, MC_U123160651, G0400713, MC_G1000734, MR/L501529/1, MC_U106179471, MC_UU_12015/2 |
| National Institute of Mental Health | P50MH060451, R01MH080295 |
| National Center for Research Resources | M01RR000096, UL1RR029893 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01NS059873, P50NS039764 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA129769 |
| National Institutes of Health/National Institute of Environmental Health Sciences | P30ES013508 |
| National Center for Advancing Translational Sciences (NCATS) | UL1TR001445, UL1TR001108, UL1TR002529 |
| Economic and Social Research Council | ES/L008238/1 |
ASJC Scopus subject areas
- General Medicine
