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 -