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

Alzheimer’s Disease Genetics Consortium, The GERAD1 Consortium, EPIC-InterAct Consortium

Research output: Contribution to journalArticle

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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 - 1 Jun 2015

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Random Allocation
Alzheimer Disease
Smoking
Odds Ratio
Mendelian Randomization Analysis
Antihypertensive Agents
Blood Pressure
Hypertension
Environmental Exposure
Genomics
Tobacco Products
Causality
LDL Cholesterol
Type 2 Diabetes Mellitus
HDL Cholesterol
Single Nucleotide Polymorphism
Insulin Resistance
Fasting
Triglycerides
Body Mass Index

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Alzheimer’s Disease Genetics Consortium, The GERAD1 Consortium, & EPIC-InterAct Consortium (2015). Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study. PLoS Medicine, 12(6), [e1001841]. https://doi.org/10.1371/journal.pmed.1001841
Alzheimer’s Disease Genetics Consortium ; The GERAD1 Consortium ; EPIC-InterAct Consortium. / Associations between Potentially Modifiable Risk Factors and Alzheimer Disease : A Mendelian Randomization Study. In: PLoS Medicine. 2015 ; Vol. 12, No. 6.
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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.",
author = "{Alzheimer’s Disease Genetics Consortium} and {The GERAD1 Consortium} and {EPIC-InterAct Consortium} and {\O}stergaard, {S{\o}ren D.} and Shubhabrata Mukherjee and Sharp, {Stephen J.} and Petroula Proitsi and Lotta, {Luca A.} and Felix Day and Perry, {John R.B.} and Boehme, {Kevin L.} and Stefan Walter and Kauwe, {John S.} and Gibbons, {Laura E.} and Larson, {Eric B.} and Powell, {John F.} and Claudia Langenberg and Crane, {Paul K.} and Wareham, {Nicholas J.} and Scott, {Robert A.} and Albert, {Marilyn S.} and Albin, {Roger L.} and Apostolova, {Liana G.} and Arnold, {Steven E.} and Sanjay Asthana and Atwood, {Craig S.} and Baldwin, {Clinton T.} and Barber, {Robert C.} and Barmada, {Michael M.} and Barnes, {Lisa L.} and Beach, {Thomas G.} and Becker, {James T.} and Beecham, {Gary W.} and Duane Beekly and Bigio, {Eileen H.} and Bird, {Thomas D.} and Deborah Blacker and Boeve, {Bradley F.} and Bowen, {James D.} and Adam Boxer and Burke, {James R.} and Buxbaum, {Joseph D.} and Cairns, {Nigel J.} and Cantwell, {Laura B.} and Chuanhai Cao and Carlson, {Chris S.} and Carlsson, {Cynthia M.} and Carney, {Regina M.} and Carrasquillo, {Minerva M.} and Carroll, {Steven L.} and Chui, {Helena C.} and Clark, {David G.} and Jason Corneveaux",
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Alzheimer’s Disease Genetics Consortium, The GERAD1 Consortium & EPIC-InterAct Consortium 2015, 'Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study', PLoS Medicine, vol. 12, no. 6, e1001841. https://doi.org/10.1371/journal.pmed.1001841

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease : A Mendelian Randomization Study. / Alzheimer’s Disease Genetics Consortium; The GERAD1 Consortium; EPIC-InterAct Consortium.

In: PLoS Medicine, Vol. 12, No. 6, e1001841, 01.06.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Associations between Potentially Modifiable Risk Factors and Alzheimer Disease

T2 - A Mendelian Randomization Study

AU - Alzheimer’s Disease Genetics Consortium

AU - The GERAD1 Consortium

AU - EPIC-InterAct Consortium

AU - Østergaard, Søren D.

AU - Mukherjee, Shubhabrata

AU - Sharp, Stephen J.

AU - Proitsi, Petroula

AU - Lotta, Luca A.

AU - Day, Felix

AU - Perry, John R.B.

AU - Boehme, Kevin L.

AU - Walter, Stefan

AU - Kauwe, John S.

AU - Gibbons, Laura E.

AU - Larson, Eric B.

AU - Powell, John F.

AU - Langenberg, Claudia

AU - Crane, Paul K.

AU - Wareham, Nicholas J.

AU - Scott, Robert A.

AU - Albert, Marilyn S.

AU - Albin, Roger L.

AU - Apostolova, Liana G.

AU - Arnold, Steven E.

AU - Asthana, Sanjay

AU - Atwood, Craig S.

AU - Baldwin, Clinton T.

AU - Barber, Robert C.

AU - Barmada, Michael M.

AU - Barnes, Lisa L.

AU - Beach, Thomas G.

AU - Becker, James T.

AU - Beecham, Gary W.

AU - Beekly, Duane

AU - Bigio, Eileen H.

AU - Bird, Thomas D.

AU - Blacker, Deborah

AU - Boeve, Bradley F.

AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Buxbaum, Joseph D.

AU - Cairns, Nigel J.

AU - Cantwell, Laura B.

AU - Cao, Chuanhai

AU - Carlson, Chris S.

AU - Carlsson, Cynthia M.

AU - Carney, Regina M.

AU - Carrasquillo, Minerva M.

AU - Carroll, Steven L.

AU - Chui, Helena C.

AU - Clark, David G.

AU - Corneveaux, Jason

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

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U2 - 10.1371/journal.pmed.1001841

DO - 10.1371/journal.pmed.1001841

M3 - Article

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VL - 12

JO - PLoS Medicine

JF - PLoS Medicine

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Alzheimer’s Disease Genetics Consortium, The GERAD1 Consortium, EPIC-InterAct Consortium. Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study. PLoS Medicine. 2015 Jun 1;12(6). e1001841. https://doi.org/10.1371/journal.pmed.1001841