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. 2023 May 1;6(5):e2313734.
doi: 10.1001/jamanetworkopen.2023.13734.

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration; Jiao Luo  1 , Jesper Qvist Thomassen  1 , Céline Bellenguez  2 , Benjamin Grenier-Boley  2 , Itziar de Rojas  3   4 , Atahualpa Castillo  5 , Kayenat Parveen  6   7 , Fahri Küçükali  8   9 , Aude Nicolas  2 , Oliver Peters  10   11 , Anja Schneider  12   13 , Martin Dichgans  14   15   16 , Dan Rujescu  17   18 , Norbert Scherbaum  19 , Deckert Jürgen  20 , Steffi Riedel-Heller  21 , Lucrezia Hausner  22 , Laura Molina Porcel  23   24 , Emrah Düzel  25   26 , Timo Grimmer  27 , Jens Wiltfang  28   29   30 , Stefanie Heilmann-Heimbach  31 , Susanne Moebus  32 , Thomas Tegos  33 , Nikolaos Scarmeas  34   35 , Jordi Clarimon  4   36 , Fermin Moreno  4   37   38 , Jordi Pérez-Tur  4   39   40 , María J Bullido  4   41   42 , Pau Pastor  43 , Raquel Sánchez-Valle  44 , Victoria Álvarez  45   46 , Mercè Boada  3   4 , Pablo García-González  3 , Raquel Puerta  3 , Pablo Mir  4   47 , Luis M Real  48   49 , Gerard Piñol-Ripoll  50   51 , Jose María García-Alberca  4   52 , Jose Luís Royo  49 , Eloy Rodriguez-Rodriguez  4   53 , Hilkka Soininen  54 , Teemu Kuulasmaa  55 , Alexandre de Mendonça  56 , Shima Mehrabian  57 , Jakub Hort  58   59 , Martin Vyhnalek  58   59 , Sven van der Lee  60   61   62 , Caroline Graff  63 , Goran Papenberg  64 , Vilmantas Giedraitis  65 , Anne Boland  66 , Delphine Bacq-Daian  66 , Jean-François Deleuze  66 , Gael Nicolas  67 , Carole Dufouil  68   69 , Florence Pasquier  70 , Olivier Hanon  71 , Stéphanie Debette  72   73 , Edna Grünblatt  74   75   76 , Julius Popp  77   78   79 , Luisa Benussi  80 , Daniela Galimberti  81   82 , Beatrice Arosio  83   84 , Patrizia Mecocci  85   86 , Vincenzo Solfrizzi  87 , Lucilla Parnetti  88 , Alessio Squassina  89 , Lucio Tremolizzo  90 , Barbara Borroni  91 , Benedetta Nacmias  92   93 , Sandro Sorbi  92   93 , Paolo Caffarra  94 , Davide Seripa  95 , Innocenzo Rainero  96 , Antonio Daniele  97   98 , Carlo Masullo  99 , Gianfranco Spalletta  100   101 , Julie Williams  102 , Philippe Amouyel  2 , Frank Jessen  6   12   103 , Patrick Kehoe  104 , Magda Tsolaki  33 , Giacomina Rossi  105 , Pascual Sánchez-Juan  4   106 , Kristel Sleegers  8   9 , Martin Ingelsson  66   107   108 , Ole A Andreassen  109   110 , Mikko Hiltunen  55 , Cornelia Van Duijn  111   112 , Rebecca Sims  5 , Wiesje van der Flier  61 , Agustín Ruiz  3   4 , Alfredo Ramirez  6   7   12   103   113 , Jean-Charles Lambert  2 , Ruth Frikke-Schmidt  1   114
Affiliations

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration et al. JAMA Netw Open. .

Erratum in

  • Errors in Author Affiliations.
    [No authors listed] [No authors listed] JAMA Netw Open. 2023 Jun 1;6(6):e2321189. doi: 10.1001/jamanetworkopen.2023.21189. JAMA Netw Open. 2023. PMID: 37273211 Free PMC article. No abstract available.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Schneider reported receiving personal fees from Biogen and Eisai outside the submitted work. Dr Rujescu reported receiving personal fees from Janssen, Gerot Lannacher, Pharmgenetix, Angelina, AC Immune, Roche, and Rovi outside the submitted work. Dr Deckert reported receiving grants from Vogel Foundation during the conduct of the study and grants from Vogel Foundation outside the submitted work. Dr Molina-Porcel reported receiving personal fees from Biogen outside the submitted work. Dr Düzel reported receiving grants from German Federal Ministry of Education and Research (BMBF), and Human Brain Project; personal fees from Roche, Biogen, and Lilly; and serving as cofounder of and owning stock in Neotiv outside the submitted work. Dr Grimmer reported receiving personal fees from AbbVie, Alector, Anavex, Biogen, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Medical Tribune, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche, Schwabe, UCB, and Vivoryon and grants from Biogen and Roche Diagnostics outside the submitted work. Dr Wiltfang reported receiving grants from BMBF during the conduct of the study and personal fees from Abbott, Biogen, Boehringer-Ingelheim, Immungenetics, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Actelion, Amgen, Beejing Yibai Science and Technology, and Roboscreen outside the submitted work; in addition, Dr Wiltfang has a patent for PCT/EP 2011 001724 issued and a patent for PCT/EP 2015 052945 issued. Dr Heilmann-Heimbach reported receiving personal fees from Life & Brain outside the submitted work. Dr Scarmeas reported receiving grants from Alzheimer’s Association, National Strategic Reference Framework, Excellence Grant, and Greek Ministry of Health during the conduct of the study and grants from Novo Nordisk and personal fees from Albert Einstein College of Medicine outside the submitted work. Dr Moreno reported receiving grants from Tau Consortium and Instituto de Salud Carlos III outside the submitted work. Dr Boada reported serving on advisory boards for Grifols, Roche, Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma outside the submitted work. Dr Soininen reported receiving personal fees from Novo Nordisk outside the submitted work. Dr Hort reported owing stock in Alzheon and receiving personal fees from Schwabe outside the submitted work. Dr Graff reported receiving grants from the Swedish Medical Research Council, Swedish Demensfonden, Swedish Alzheimer Foundation, Swedish Brain Foundation, Region Stockholm County ALF Project, and Karolinska Institutet StratNeuro during the conduct of the study. Dr Popp reported receiving grants from the Swiss National Research Foundation and Synapsis Foundation Switzerland during the conduct of the study and personal fees from OM Pharma Switzerland, Dr Schwabe Pharma Switzerland, and Roche outside the submitted work. Dr Spalletta reported receiving grants from the Italian Ministry of Health during the conduct of the study. Dr Amouyel reported receiving personal fees from Fondation Alzheimer and Genoscreen Biotech outside the submitted work. Dr Ingelsson reported receiving personal fees from BioArctic outside the submitted work. Dr Andreassen reported receiving grants from KG Jebsen Stiftelsen, South East Norway Health Authority, Research Council of Norway, and European Union Horizon 2020 during the conduct of the study and personal fees from HealthLytix, Lundbeck, and Sunovion outside the submitted work. Dr van der Flier reported receiving grants from Netherlands Organisation for Health Research and Development and European Alzheimer’s Disease DNA Biobank during the conduct of the study; grants from Alzheimer Nederland, Hersenstichting, CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis-NL, Life-MI, Avid Radiopharmaceuticals, Roche BV, Fujifilm, Combinostics, Gieskes-Strijbis, Dioraphte, Edwin Bouw, Equilibrio, and Pasman; personal fees from Boehringer Ingelheim, Biogen, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare; performing contract research for Biogen and Boehringer Ingelheim; is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA; serving on advisory boards for Biogen and Roche; and serving as associate editor of Alzheimer, Research and Therapy (in 2020-2021) and Brain outside the submitted work. Dr Ramirez reported receiving grants from BMBF during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Schematic Overview of the Study Design
AD indicates Alzheimer disease; apoA1, apolipoprotein A1; apoB, apolipoprotein B; BMI, body mass index; EADB, European Alzheimer & Dementia Biobank; GWAS, genome-wide association study; HDL, high-density lipoprotein; IVW, inverse-variance weighted; LDL, low-density lipoprotein; MR, mendelian randomization; MR-PRESSO, mendelian randomization pleiotropy residual sum and outlier; SNV, single nucleotide variant; TG, triglycerides; UKB, UK Biobank.
Figure 2.
Figure 2.. Associations of Genetically Determined Modifiable Risk Factors and Alzheimer Disease (AD) in the European Alzheimer & Dementia Biobank Data Set of Participants With Clinically Diagnosed AD
Multivariable mendelian randomization was performed for correlated phenotypes only (lipid traits and blood pressure). ApoA1 indicates apolipoprotein A1; apoB, apolipoprotein B; BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; IVW, inverse-variance weighted; LDL, low-density lipoprotein; MR-PRESSO, mendelian randomization pleiotropy residual sum and outlier; OR, odds ratio; SBP, systolic blood pressure; SNV, single nucleotide variant; TG, triglycerides.
Figure 3.
Figure 3.. Associations of Genetically Determined Modifiable Risk Factors and Alzheimer Disease (AD) in the European Alzheimer & Dementia Biobank Data Set Excluding the Entire UK Biobank
Multivariable mendelian randomization was performed for correlated phenotypes only (lipid traits and blood pressure). Abbreviations: apoA1, apolipoprotein A1; apoB, apolipoprotein B; BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; IVW, inverse-variance weighted; LDL, low-density lipoprotein cholesterol; MR-PRESSO, mendelian randomization pleiotropy residual sum and outlier; OR, odds ratio; SBP, systolic blood pressure; SNV, single nucleotide variant; TG, triglycerides.
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References

    1. Livingston G, Huntley J, Sommerlad A, et al. . Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6 - DOI - PMC - PubMed
    1. Guidelines WHO; Approved by the Guidelines Review Committee . Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. World Health Organization; 2019. - PubMed
    1. Chowdhary N, Barbui C, Anstey KJ, et al. . Reducing the risk of cognitive decline and dementia: WHO recommendations. Front Neurol. 2022;12:765584. doi:10.3389/fneur.2021.765584 - DOI - PMC - PubMed
    1. Singh-Manoux A, Dugravot A, Shipley M, et al. . Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study. Alzheimers Dement. 2018;14(2):178-186. doi:10.1016/j.jalz.2017.06.2637 - DOI - PMC - PubMed
    1. Abell JG, Kivimäki M, Dugravot A, et al. . Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension. Eur Heart J. 2018;39(33):3119-3125. doi:10.1093/eurheartj/ehy288 - DOI - PMC - PubMed

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