Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.

Autor:	Luo J; Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Thomassen JQ; Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Bellenguez C; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France., Grenier-Boley B; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France., de Rojas I; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain., Castillo A; Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Wales, United Kingdom., Parveen K; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Department of Neurodegenerative diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany., Küçükali F; Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, Antwerp, Belgium.; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Nicolas A; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France., Peters O; German Center for Neurodegenerative Diseases, Berlin, Germany.; Institute of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin, Germany., Schneider A; German Center for Neurodegenerative Diseases, Bonn, Germany.; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany., Dichgans M; Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.; German Center for Neurodegenerative Diseases, Munich, Germany.; Munich Cluster for Systems Neurology, Munich, Germany., Rujescu D; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.; Comprehensive Centre for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria., Scherbaum N; LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany., Jürgen D; Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany., Riedel-Heller S; Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany., Hausner L; Department of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Heidelberg, Germany., Porcel LM; Neurological Tissue Bank, Biobanc Hospital Clinic, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Barcelona, Spain.; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clinic, Barcelona, Spain., Düzel E; German Center for Neurodegenerative Diseases, Magdeburg, Germany.; Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg, Germany., Grimmer T; Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Psychiatry and Psychotherapy, Munich, Germany., Wiltfang J; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen, Germany.; German Center for Neurodegenerative Diseases, Goettingen, Germany.; Medical Science Department, Instituto de Biomedicina, Aveiro, Portugal., Heilmann-Heimbach S; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Moebus S; Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany., Tegos T; First Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece., Scarmeas N; First Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.; Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, New York., Clarimon J; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain., Moreno F; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.; Neurosciences Area, Instituto Biodonostia, San Sebastian, Spain., Pérez-Tur J; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Unitat de Genètica Molecular, Institut de Biomedicina de València, Consejo Superior de Investigaciones Científicas, Valencia, Spain.; Unidad Mixta de Neurologia Genètica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain., Bullido MJ; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Madrid, Spain.; Instituto de Investigacion Sanitaria Hospital la Paz, Madrid, Spain., Pastor P; Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain., Sánchez-Valle R; Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain., Álvarez V; Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain.; Instituto de Investigación Sanitaria del Principado de Asturias, Asturias, Spain., Boada M; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain., García-González P; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain., Puerta R; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain., Mir P; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, Spain., Real LM; Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain.; Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain., Piñol-Ripoll G; Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain.; Institut de Recerca Biomedica de Lleida, Lleida, Spain., García-Alberca JM; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Alzheimer Research Center & Memory Clinic, Instituto Andaluz de Neurociencia, Málaga, Spain., Royo JL; Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain., Rodriguez-Rodriguez E; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Neurology Service, Marqués de Valdecilla University Hospital, University of Cantabria and IDIVAL, Santander, Spain., Soininen H; Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland., Kuulasmaa T; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland., de Mendonça A; Faculty of Medicine, University of Lisbon, Portugal., Mehrabian S; Clinic of Neurology, UH 'Alexandrovska,' Medical University-Sofia, Sofia, Bulgaria., Hort J; Memory Clinic, Department of Neurology, Charles University, Second Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.; International Clinical Research Center, St Anne's University Hospital Brno, Brno, Czech Republic., Vyhnalek M; Memory Clinic, Department of Neurology, Charles University, Second Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.; International Clinical Research Center, St Anne's University Hospital Brno, Brno, Czech Republic., van der Lee S; Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, locatie VUmc, Amsterdam, the Netherlands.; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, locatie VUmc, Amsterdam, the Netherlands.; Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands., Graff C; Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital-Solna, Stockholm, Sweden., Papenberg G; Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden., Giedraitis V; Department of Public Health and Caring Sciences/ and Geriatrics, Uppsala University, Uppsala, Sweden., Boland A; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France., Bacq-Daian D; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France., Deleuze JF; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France., Nicolas G; Normandie Univ, Université de Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Centre national de référence pour les malades Alzheimer jeunes, Rouen, France., Dufouil C; Inserm, Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, ISPED, CIC 1401-EC, Bordeaux, France.; CHU de Bordeaux, Pole santé publique, Bordeaux, France., Pasquier F; University of Lille, Inserm, CHU Lille, UMR1172, Resources and Research Memory Center of Distalz, Licend, Lille, France., Hanon O; Université de Paris, EA 4468, Assistance Publique - Hôpitaux de Paris, Hôpital Broca, Paris, France., Debette S; University Bordeaux, Inserm, Bordeaux Population Health Research Center, France.; Department of Neurology, Bordeaux University Hospital, Bordeaux, France., Grünblatt E; Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland.; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland., Popp J; Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.; Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland.; Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zurich, Switzerland., Benussi L; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy., Galimberti D; Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.; Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy., Arosio B; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.; Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Mecocci P; Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.; Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden., Solfrizzi V; Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unit, University of Bari Aldo Moro, Bari, Italy., Parnetti L; Centre for Memory Disturbances, Lab of Clinical Neurochemistry, Section of Neurology, University of Perugia, Perugia, Italy., Squassina A; Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy., Tremolizzo L; Neurology Unit, Hospital San Gerardo, Monza and University of Milano-Bicocca, Milan, Italy., Borroni B; Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy., Nacmias B; Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy.; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy., Sorbi S; Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy.; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy., Caffarra P; Unit of Neurology, University of Parma, Parma, Italy., Seripa D; Laboratory for Advanced Hematological Diagnostics, Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy., Rainero I; Department of Neuroscience Rita Levi Montalcini, University of Torino, Torino, Italy., Daniele A; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.; Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy., Masullo C; Institute of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy., Spalletta G; Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.; Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas., Williams J; UK Dementia Research Institute at Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom., Amouyel P; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France., Jessen F; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; German Center for Neurodegenerative Diseases, Bonn, Germany.; Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany., Kehoe P; Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom., Tsolaki M; First Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece., Rossi G; Unit of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Sánchez-Juan P; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.; Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, Spain., Sleegers K; Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, Antwerp, Belgium.; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Ingelsson M; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France.; Krembil Brain Institute, University Health Network, Toronto, Canada.; Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada., Andreassen OA; NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Hiltunen M; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland., Van Duijn C; Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.; Nuffield Department of Population Health, Oxford University, Oxford, United Kingdom., Sims R; Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Wales, United Kingdom., van der Flier W; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, locatie VUmc, Amsterdam, the Netherlands., Ruiz A; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.; Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain., Ramirez A; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Department of Neurodegenerative diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany.; German Center for Neurodegenerative Diseases, Bonn, Germany.; Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.; Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, Texas., Lambert JC; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France., Frikke-Schmidt R; Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	JAMA network open [JAMA Netw Open] 2023 May 01; Vol. 6 (5), pp. e2313734. Date of Electronic Publication: 2023 May 01.
DOI:	10.1001/jamanetworkopen.2023.13734
Abstrakt:	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.
Databáze:	MEDLINE
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