Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
Question What are the genetic associations between modifiable risk factors and Alzheimer disease (AD)?
Findings In this genetic association study using a mendelian randomization framework with the largest genomic data sets to date, including 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD, genetically determined increased high-density lipoprotein cholesterol and increased systolic blood pressure were associated with higher risk of AD.
Meaning These findings suggest that genetically determined increased high-density lipoprotein cholesterol and systolic blood pressure may be involved in AD pathogenesis, which may thus inspire new drug targeting and improved early dementia prevention.
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.
JAMA Netw Open. 2023;6(5):e2313734. doi:10.1001/jamanetworkopen.2023.13734
Date: May 17, 2023
Link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805006
European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration
Corresponding Author: Ruth Frikke-Schmidt, MD, DMSc, PhD, Department of Clinical Biochemistry, Copenhagen University Hospital–Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (ruth.frikke-schmidt@regionh.dk).
Author Contributions: Drs Luo and Frikke-Schmidt had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Luo, Thomassen, Dichgans, Rujescu, Hausner, Düzel, Tegos, Boada, Nacmias, Daniele, Tsolaki, Ingelsson, Frikke-Schmidt.
Acquisition, analysis, or interpretation of data: Luo, Thomassen, Bellenguez, Grenier-Boley, de Rojas, Castillo Morales, Parveen, Küçükali, A. Nicolas, Peters, Schneider, Dichgans, Scherbaum, Deckert, Riedel-Heller, Hausner, Molina-Porcel, Düzel, Grimmer, Wiltfang, Heilmann-Heimbach, Moebus, Scarmeas, Clarimon, Moreno, Perez-Tur, Bullido, Pastor, Sánchez-Valle, Alvarez, Boada, García-González, Puerta Fuentes, Mir, Real, Piñol-Ripoll, García-Alberca, Royo, Rodríguez-Rodriguez, Soininen, Kuulasmaa, de Mendonça, Mehrabian, Hort, Vyhnalek, van der Lee, Graff, Papenberg, Giedraitis, Boland, Bacq-Daian, Deleuze, G. Nicolas, Dufouil, Pasquier, Hanon, Debette, Grünblatt, Popp, Benussi, Galimberti, Arosio, Mecocci, Solfrizzi, Parnetti, Squassina, Tremolizzo, Borroni, Sorbi, Caffarra, Seripa, Rainero, Masullo, Spalletta, Williams, Amouyel, Jessen, Kehoe, Rossi, Sánchez-Juan, Sleegers, Andreassen, Hiltunen, van Duijn, Sims, van der Flier, Ruiz, Ramirez, Lambert, Frikke-Schmidt.
Drafting of the manuscript: Luo, Dichgans, Boada, Kuulasmaa, Tsolaki, Hiltunen, Frikke-Schmidt.
Critical revision of the manuscript for important intellectual content: Luo, Thomassen, Bellenguez, Grenier-Boley, de Rojas, Castillo Morales, Parveen, Küçükali, A. Nicolas, Peters, Schneider, Dichgans, Rujescu, Scherbaum, Deckert, Riedel-Heller, Hausner, Molina-Porcel, Düzel, Grimmer, Wiltfang, Heilmann-Heimbach, Moebus, Tegos, Scarmeas, Clarimon, Moreno, Perez-Tur, Bullido, Pastor, Sánchez-Valle, Alvarez, Boada, García-González, Puerta Fuentes, Mir, Real, Piñol-Ripoll, García-Alberca, Royo, Rodríguez-Rodriguez, Soininen, de Mendonça, Mehrabian, Hort, Vyhnalek, van der Lee, Graff, Papenberg, Giedraitis, Boland, Bacq-Daian, Deleuze, G. Nicolas, Dufouil, Pasquier, Hanon, Debette, Grünblatt, Popp, Benussi, Galimberti, Arosio, Mecocci, Solfrizzi, Parnetti, Squassina, Tremolizzo, Borroni, Nacmias, Sorbi, Caffarra, Seripa, Rainero, Daniele, Masullo, Spalletta, Williams, Amouyel, Jessen, Kehoe, Rossi, Sánchez-Juan, Sleegers, Ingelsson, Andreassen, van Duijn, Sims, van der Flier, Ruiz, Ramirez, Lambert, Frikke-Schmidt.
Statistical analysis: Luo, Thomassen, Bellenguez, Castillo Morales, Parveen, Tegos, Real, Kuulasmaa, van der Lee, Amouyel, van Duijn.
Obtained funding: Deckert, Riedel-Heller, Düzel, Scarmeas, Clarimon, Graff, G. Nicolas, Dufouil, Debette, Popp, Benussi, Sorbi, Spalletta, Williams, Jessen, Sánchez-Juan, Sleegers, Andreassen, van Duijn, Sims, Ruiz, Ramirez, Lambert, Frikke-Schmidt.
Administrative, technical, or material support: Bellenguez, Grenier-Boley, Schneider, Molina-Porcel, Grimmer, Heilmann-Heimbach, Moreno, Pastor, Royo, Soininen, Vyhnalek, Graff, Papenberg, Giedraitis, Boland, Deleuze, G. Nicolas, Popp, Galimberti, Mecocci, Tremolizzo, Seripa, Daniele, Williams, Amouyel, Tsolaki, Ingelsson, Andreassen, Sims, Ruiz, Lambert, Frikke-Schmidt.
Supervision: Thomassen, Riedel-Heller, Düzel, Wiltfang, Scarmeas, Mir, Piñol-Ripoll, García-Alberca, Rodríguez-Rodriguez, Mehrabian, Boland, Arosio, Mecocci, Solfrizzi, Parnetti, Nacmias, Caffarra, Rainero, Masullo, Jessen, Sleegers, Hiltunen, van Duijn, Ruiz, Lambert, Frikke-Schmidt.
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