Genetic Associations between Modifiable Risk Factors and Alzheimer Disease: [Inkl. correction]
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Genetic Associations between Modifiable Risk Factors and Alzheimer Disease : [Inkl. correction]. / Luo, Jiao; Thomassen, Jesper Qvist; Bellenguez, Céline; Grenier-Boley, Benjamin; De Rojas, Itziar; Castillo, Atahualpa; Parveen, Kayenat; Küçükali, Fahri; Nicolas, Aude; Peters, Oliver; Schneider, Anja; Dichgans, Martin; Rujescu, Dan; Scherbaum, Norbert; Jürgen, Deckert; Riedel-Heller, Steffi; Hausner, Lucrezia; Porcel, Laura Molina; Düzel, Emrah; Grimmer, Timo; Wiltfang, Jens; Heilmann-Heimbach, Stefanie; Moebus, Susanne; Tegos, Thomas; Scarmeas, Nikolaos; Clarimon, Jordi; Moreno, Fermin; Pérez-Tur, Jordi; Bullido, María J.; Pastor, Pau; Sánchez-Valle, Raquel; Álvarez, Victoria; Boada, Mercè; García-González, Pablo; Puerta, Raquel; Mir, Pablo; Real, Luis M.; Piñol-Ripoll, Gerard; García-Alberca, Jose María; Royo, Jose Luís; Rodriguez-Rodriguez, Eloy; Soininen, Hilkka; Kuulasmaa, Teemu; De Mendonça, Alexandre; Mehrabian, Shima; Hort, Jakub; Vyhnalek, Martin; Van Der Lee, Sven; Graff, Caroline; Papenberg, Goran; Giedraitis, Vilmantas; Boland, Anne; Bacq-Daian, Delphine; Deleuze, Jean François; Nicolas, Gael; Dufouil, Carole; Pasquier, Florence; Hanon, Olivier; Debette, Stéphanie; Grünblatt, Edna; Popp, Julius; Benussi, Luisa; Galimberti, Daniela; Arosio, Beatrice; Mecocci, Patrizia; Solfrizzi, Vincenzo; Parnetti, Lucilla; Squassina, Alessio; Tremolizzo, Lucio; Borroni, Barbara; Nacmias, Benedetta; Sorbi, Sandro; Caffarra, Paolo; Seripa, Davide; Rainero, Innocenzo; Daniele, Antonio; Masullo, Carlo; Spalletta, Gianfranco; Williams, Julie; Amouyel, Philippe; Jessen, Frank; Kehoe, Patrick; Magda, Tsolaki; Rossi, Giacomina; Sánchez-Juan, Pascual; Sleegers, Kristel; Ingelsson, Martin; Andreassen, Ole A.; Hiltunen, Mikko; Van Duijn, Cornelia; Sims, Rebecca; Van Der Flier, Wiesje; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean Charles; Frikke-Schmidt, Ruth.
I: JAMA network open, Bind 6, Nr. 5, e2313734, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Genetic Associations between Modifiable Risk Factors and Alzheimer Disease
T2 - [Inkl. correction]
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 - Papenberg, Goran
AU - Giedraitis, Vilmantas
AU - Boland, Anne
AU - Bacq-Daian, Delphine
AU - Deleuze, Jean François
AU - Nicolas, Gael
AU - Dufouil, Carole
AU - Pasquier, Florence
AU - Hanon, Olivier
AU - Debette, Stéphanie
AU - Grünblatt, Edna
AU - Popp, Julius
AU - Benussi, Luisa
AU - Galimberti, Daniela
AU - Arosio, Beatrice
AU - Mecocci, Patrizia
AU - Solfrizzi, Vincenzo
AU - Parnetti, Lucilla
AU - Squassina, Alessio
AU - Tremolizzo, Lucio
AU - Borroni, Barbara
AU - Nacmias, Benedetta
AU - Sorbi, Sandro
AU - Caffarra, Paolo
AU - Seripa, Davide
AU - Rainero, Innocenzo
AU - Daniele, Antonio
AU - Masullo, Carlo
AU - Spalletta, Gianfranco
AU - Williams, Julie
AU - Amouyel, Philippe
AU - Jessen, Frank
AU - Kehoe, Patrick
AU - Magda, Tsolaki
AU - Rossi, Giacomina
AU - Sánchez-Juan, Pascual
AU - Sleegers, Kristel
AU - Ingelsson, Martin
AU - Andreassen, Ole A.
AU - Hiltunen, Mikko
AU - Van Duijn, Cornelia
AU - Sims, Rebecca
AU - Van Der Flier, Wiesje
AU - Ruiz, Agustín
AU - Ramirez, Alfredo
AU - Lambert, Jean Charles
AU - Frikke-Schmidt, Ruth
N1 - Publisher Copyright: © 2023 American Medical Association. All rights reserved.
PY - 2023
Y1 - 2023
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 39106 participants with clinically diagnosed AD and 401577 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 39106 participants with clinically diagnosed AD and 401577 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.
U2 - 10.1001/jamanetworkopen.2023.13734
DO - 10.1001/jamanetworkopen.2023.13734
M3 - Journal article
C2 - 37195665
AN - SCOPUS:85159768599
VL - 6
JO - JAMA network open
JF - JAMA network open
SN - 2574-3805
IS - 5
M1 - e2313734
ER -
ID: 348165851