Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
Authors:   European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration, 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 , Tsolaki Magda , 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 
Published: May 2023

ImportanceAn 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.ObjectiveTo comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.Design, Setting, and ParticipantsThis 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 &amp;amp; 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.ExposuresGenetically determined modifiable risk factors.Main Outcomes and MeasuresOdds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.ResultsThe 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 RelevanceThis 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.