Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Jiao Luo; Jesper Qvist Thomassen; Céline Bellenguez; Benjamin Grenier-Boley; Itziar de Rojas; Atahualpa Castillo; Kayenat Parveen; Fahri Küçükali; Aude Nicolas; Oliver Peters; Anja Schneider; Martin Dichgans; Dan Rujescu; Norbert Scherbaum; Deckert Jürgen; Steffi Riedel-Heller; Lucrezia Hausner; Laura Molina Porcel; Emrah Düzel; Timo Grimmer; Jens Wiltfang; Stefanie Heilmann-Heimbach; Susanne Moebus; Thomas Tegos; Nikolaos Scarmeas; Jordi Clarimon; Fermin Moreno; Jordi Pérez-Tur; María J Bullido; Pau Pastor; Raquel Sánchez-Valle; Victoria Álvarez; Mercè Boada; Pablo García-González; Raquel Puerta; Pablo Mir; Luis M Real; Gerard Piñol-Ripoll; Jose María García-Alberca; Jose Luís Royo; Eloy Rodriguez-Rodriguez; Hilkka Soininen; Teemu Kuulasmaa; Alexandre de Mendonça; Shima Mehrabian; Jakub Hort; Martin Vyhnalek; Sven van der Lee; Caroline Graff; Ruth Frikke-Schmidt; European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration

doi:10.1001/jamanetworkopen.2023.13734

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Jiao Luo, Jesper Qvist Thomassen, Céline Bellenguez, Benjamin Grenier-Boley, Itziar de Rojas, Atahualpa Castillo, Kayenat Parveen, Fahri Küçükali, Aude Nicolas, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Deckert Jürgen, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina Porcel, Emrah Düzel, Timo GrimmerJens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Jordi Clarimon, Fermin Moreno, Jordi Pérez-Tur, María J Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Jose Luís Royo, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Teemu Kuulasmaa, Alexandre de Mendonça, Shima Mehrabian, Jakub Hort, Martin Vyhnalek, Sven van der Lee, Caroline Graff, Ruth Frikke-Schmidt^*, European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration

^*Corresponding author for this work

Department of Clinical Biochemistry

76 Citations (Scopus)

Abstract

IMPORTANCE: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.

OBJECTIVE: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.

DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.

EXPOSURES: Genetically determined modifiable risk factors.

MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.

RESULTS: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).

CONCLUSIONS AND RELEVANCE: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Original language	English
Article number	e13734
Journal	JAMA network open
Volume	6
Issue number	5
Pages (from-to)	e2313734
ISSN	2574-3805
DOIs	https://doi.org/10.1001/jamanetworkopen.2023.13734
Publication status	Published - 1 May 2023

Access to Document

10.1001/jamanetworkopen.2023.13734

Cite this

Luo, J., Thomassen, J. Q., Bellenguez, C., Grenier-Boley, B., de Rojas, I., Castillo, A., Parveen, K., Küçükali, F., Nicolas, A., Peters, O., Schneider, A., Dichgans, M., Rujescu, D., Scherbaum, N., Jürgen, D., Riedel-Heller, S., Hausner, L., Porcel, L. M., Düzel, E., ... European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration (2023). Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease. JAMA network open, 6(5), e2313734. Article e13734. https://doi.org/10.1001/jamanetworkopen.2023.13734

Luo, J , Thomassen, JQ, Bellenguez, C, Grenier-Boley, B, de Rojas, I, Castillo, A, Parveen, K, Küçükali, F, Nicolas, A, Peters, O, Schneider, A, Dichgans, M, Rujescu, D, Scherbaum, N, Jürgen, D, Riedel-Heller, S, Hausner, L, Porcel, LM, Düzel, E, Grimmer, T, Wiltfang, J, Heilmann-Heimbach, S, Moebus, S, Tegos, T, Scarmeas, N, Clarimon, J, Moreno, F, Pérez-Tur, J, Bullido, MJ, Pastor, P, Sánchez-Valle, R, Álvarez, V, Boada, M, García-González, P, Puerta, R, Mir, P, Real, LM, Piñol-Ripoll, G, García-Alberca, JM, Royo, JL, Rodriguez-Rodriguez, E, Soininen, H, Kuulasmaa, T, de Mendonça, A, Mehrabian, S, Hort, J, Vyhnalek, M, van der Lee, S, Graff, C, Frikke-Schmidt, R & European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration 2023, 'Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease', JAMA network open, vol. 6, no. 5, e13734, pp. e2313734. https://doi.org/10.1001/jamanetworkopen.2023.13734

@article{a3c86a7fbacb42fe853eeed654ff6256,

title = "Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease",

abstract = "IMPORTANCE: An estimated 40\% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer \& Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES: Genetically determined modifiable risk factors.MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95\% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54\% to 75\% were female, and among control participants, 48\% to 60\% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95\% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95\% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95\% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95\% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.",

author = "Jiao Luo and Thomassen, \{Jesper Qvist\} and C{\'e}line Bellenguez and Benjamin Grenier-Boley and \{de Rojas\}, Itziar and Atahualpa Castillo and Kayenat Parveen and Fahri K{\"u}{\c c}{\"u}kali and Aude Nicolas and Oliver Peters and Anja Schneider and Martin Dichgans and Dan Rujescu and Norbert Scherbaum and Deckert J{\"u}rgen and Steffi Riedel-Heller and Lucrezia Hausner and Porcel, \{Laura Molina\} and Emrah D{\"u}zel and Timo Grimmer and Jens Wiltfang and Stefanie Heilmann-Heimbach and Susanne Moebus and Thomas Tegos and Nikolaos Scarmeas and Jordi Clarimon and Fermin Moreno and Jordi P{\'e}rez-Tur and Bullido, \{Mar{\'i}a J\} and Pau Pastor and Raquel S{\'a}nchez-Valle and Victoria {\'A}lvarez and Merc{\`e} Boada and Pablo Garc{\'i}a-Gonz{\'a}lez and Raquel Puerta and Pablo Mir and Real, \{Luis M\} and Gerard Pi{\~n}ol-Ripoll and Garc{\'i}a-Alberca, \{Jose Mar{\'i}a\} and Royo, \{Jose Lu{\'i}s\} and Eloy Rodriguez-Rodriguez and Hilkka Soininen and Teemu Kuulasmaa and \{de Mendon{\c c}a\}, Alexandre and Shima Mehrabian and Jakub Hort and Martin Vyhnalek and \{van der Lee\}, Sven and Caroline Graff and Ruth Frikke-Schmidt and \{European Alzheimer{\textquoteright}s \& Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration\}",

year = "2023",

month = may,

day = "1",

doi = "10.1001/jamanetworkopen.2023.13734",

language = "English",

volume = "6",

pages = "e2313734",

journal = "JAMA network open",

issn = "2574-3805",

publisher = "American Medical Association",

number = "5",

}

TY - JOUR

T1 - Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

AU - Luo, Jiao

AU - Thomassen, Jesper Qvist

AU - Bellenguez, Céline

AU - Grenier-Boley, Benjamin

AU - de Rojas, Itziar

AU - Castillo, Atahualpa

AU - Parveen, Kayenat

AU - Küçükali, Fahri

AU - Nicolas, Aude

AU - Peters, Oliver

AU - Schneider, Anja

AU - Dichgans, Martin

AU - Rujescu, Dan

AU - Scherbaum, Norbert

AU - Jürgen, Deckert

AU - Riedel-Heller, Steffi

AU - Hausner, Lucrezia

AU - Porcel, Laura Molina

AU - Düzel, Emrah

AU - Grimmer, Timo

AU - Wiltfang, Jens

AU - Heilmann-Heimbach, Stefanie

AU - Moebus, Susanne

AU - Tegos, Thomas

AU - Scarmeas, Nikolaos

AU - Clarimon, Jordi

AU - Moreno, Fermin

AU - Pérez-Tur, Jordi

AU - Bullido, María J

AU - Pastor, Pau

AU - Sánchez-Valle, Raquel

AU - Álvarez, Victoria

AU - Boada, Mercè

AU - García-González, Pablo

AU - Puerta, Raquel

AU - Mir, Pablo

AU - Real, Luis M

AU - Piñol-Ripoll, Gerard

AU - García-Alberca, Jose María

AU - Royo, Jose Luís

AU - Rodriguez-Rodriguez, Eloy

AU - Soininen, Hilkka

AU - Kuulasmaa, Teemu

AU - de Mendonça, Alexandre

AU - Mehrabian, Shima

AU - Hort, Jakub

AU - Vyhnalek, Martin

AU - van der Lee, Sven

AU - Graff, Caroline

AU - Frikke-Schmidt, Ruth

AU - European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration

PY - 2023/5/1

Y1 - 2023/5/1

N2 - IMPORTANCE: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES: Genetically determined modifiable risk factors.MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

AB - IMPORTANCE: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES: Genetically determined modifiable risk factors.MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

UR - https://www.scopus.com/pages/publications/85159768599

U2 - 10.1001/jamanetworkopen.2023.13734

DO - 10.1001/jamanetworkopen.2023.13734

M3 - Journal article

C2 - 37195665

SN - 2574-3805

VL - 6

SP - e2313734

JO - JAMA network open

JF - JAMA network open

IS - 5

M1 - e13734

ER -

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Abstract

Access to Document

Other files and links

Fingerprint

Cite this