Meta-Analysis

. 2022 Nov;144(5):821-842.

doi: 10.1007/s00401-022-02454-z. Epub 2022 Sep 6.

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Iris E Jansen^#^{1

2

3}, Sven J van der Lee^#^{4

5

6}, Duber Gomez-Fonseca^#^{7

8

9}, Itziar de Rojas^#^{10

11}, Maria Carolina Dalmasso^#^{12

13}, Benjamin Grenier-Boley^#¹⁴, Anna Zettergren¹⁵, Aniket Mishra¹⁶, Muhammad Ali^{7

8

9}, Victor Andrade^{12

17}, Céline Bellenguez¹⁴, Luca Kleineidam^{12

17

18}, Fahri Küçükali^{19

20}, Yun Ju Sung^{7

8

9}, Niccolo Tesí^{4

5

6}, Ellen M Vromen^{4

5}, Douglas P Wightman²¹, Daniel Alcolea^{11

22}, Montserrat Alegret^{10

11}, Ignacio Alvarez^{23

24}, Philippe Amouyel¹⁴, Lavinia Athanasiu²⁵, Shahram Bahrami²⁵, Henri Bailly²⁶, Olivia Belbin^{11

22}, Sverre Bergh^{27

28}, Lars Bertram²⁹, Geert Jan Biessels³⁰, Kaj Blennow^{31

32}, Rafael Blesa^{11

22}, Mercè Boada^{10

11}, Anne Boland³³, Katharina Buerger^{34

35}, Ángel Carracedo^{36

37}, Laura Cervera-Carles^{11

22}, Geneviève Chene^{16

38}, Jurgen A H R Claassen^{39

40}, Stephanie Debette^{16

38

41}, Jean-Francois Deleuze³³, Peter Paul de Deyn⁴², Janine Diehl-Schmid^{43

44}, Srdjan Djurovic^{45

46}, Oriol Dols-Icardo^{11

22}, Carole Dufouil^{16

47}, Emmanuelle Duron⁴⁸, Emrah Düzel^{49

50}; EADB consortium; Tormod Fladby^{51

52}, Juan Fortea^{11

22}, Lutz Frölich⁵³, Pablo García-González^{10

11}, Maria Garcia-Martinez⁵⁴, Ina Giegling⁵⁵, Oliver Goldhardt⁴³, Johan Gobom³², Timo Grimmer⁴³, Annakaisa Haapasalo⁵⁶, Harald Hampel^{57

58}, Olivier Hanon^{26

59}, Lucrezia Hausner⁵³, Stefanie Heilmann-Heimbach⁶⁰, Seppo Helisalmi⁶¹, Michael T Heneka^{17

18}, Isabel Hernández^{10

11}, Sanna-Kaisa Herukka⁶², Henne Holstege^{4

5

6}, Jonas Jarholm⁵², Silke Kern^{15

63}, Anne-Brita Knapskog⁶⁴, Anne M Koivisto^{62

65

66}, Johannes Kornhuber⁶⁷, Teemu Kuulasmaa⁶⁸, Carmen Lage^{54

69}, Christoph Laske^{70

71}, Ville Leinonen^{72

73}, Piotr Lewczuk^{67

74}, Alberto Lleó^{11

22}, Adolfo López de Munain^{11

75

76

77}, Sara Lopez-Garcia⁵⁴, Wolfgang Maier¹⁷, Marta Marquié^{10

11}, Merel O Mol⁷⁸, Laura Montrreal¹⁰, Fermin Moreno^{11

75

76}, Sonia Moreno-Grau^{10

11}, Gael Nicolas⁷⁹, Markus M Nöthen⁶⁰, Adelina Orellana^{10

11}, Lene Pålhaugen^{51

52}, Janne M Papma⁷⁸, Florence Pasquier¹⁴, Robert Perneczky^{34

80

81

82}, Oliver Peters^{49

83}, Yolande A L Pijnenburg^{4

5}, Julius Popp^{84

85}, Danielle Posthuma²¹, Ana Pozueta⁵⁴, Josef Priller^{83

86

87}, Raquel Puerta¹⁰, Inés Quintela³⁶, Inez Ramakers⁸⁸, Eloy Rodriguez-Rodriguez⁵⁴, Dan Rujescu⁵⁵, Ingvild Saltvedt^{89

90}, Pascual Sanchez-Juan⁹¹, Philip Scheltens^{4

5}, Norbert Scherbaum⁹², Matthias Schmid⁹³, Anja Schneider^{17

18}, Geir Selbæk^{28

51

64}, Per Selnes⁵², Alexey Shadrin²⁵, Ingmar Skoog^{15

63}, Hilkka Soininen⁶², Lluís Tárraga^{10

11}, Stefan Teipel^{94

95}; GR@ACE study group; Betty Tijms^{4

5}, Magda Tsolaki⁹⁶, Christine Van Broeckhoven^{20

97}, Jasper Van Dongen^{19

20}, John C van Swieten⁷⁸, Rik Vandenberghe^{98

99}, Jean-Sébastien Vidal²⁶, Pieter J Visser^{4

5

100

101}, Jonathan Vogelgsang^{102

103}, Margda Waern^{15

104}, Michael Wagner^{17

18}, Jens Wiltfang^{102

105

106}, Mandy M J Wittens^{20

107}, Henrik Zetterberg^{31

32

108

109

110}, Miren Zulaica^{11

75

76}, Cornelia M van Duijn^{111

112}, Maria Bjerke^{20

107

113}, Sebastiaan Engelborghs^{20

107

113

114}, Frank Jessen^{18

115

116}, Charlotte E Teunissen^{5

117}, Pau Pastor¹¹⁸, Mikko Hiltunen¹¹⁹, Martin Ingelsson^{120

121

122}, Ole A Andreassen^{25

123}, Jordi Clarimón^{11

22}, Kristel Sleegers^{19

20}, Agustín Ruiz^#^{10

11}, Alfredo Ramirez^#^{12

17

18

116

124}, Carlos Cruchaga^#^{7

8

9}, Jean-Charles Lambert^#¹⁴, Wiesje van der Flier^#^{125

126}

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands. i.e.jansen@vu.nl.
² Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands. i.e.jansen@vu.nl.
³ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, The Netherlands. i.e.jansen@vu.nl.
⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.
⁵ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
⁶ Section Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.
⁷ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁸ NeuroGenomics and Informatics, Washington University School of Medicine, St Louis, MO, USA.
⁹ Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.
¹⁰ Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
¹¹ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹² Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³ Neurosciences and Complex Systems Unit (ENyS), CONICET, Hospital El Cruce, National University A. Jauretche (UNAJ), Florencio Varela, Argentina.
¹⁴ Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE / Labex DISTALZ - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000, Lille, France.
¹⁵ Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden.
¹⁶ University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, 33000, Bordeaux, France.
¹⁷ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany.
¹⁸ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁹ Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
²⁰ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
²¹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, The Netherlands.
²² Sant Pau Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
²³ Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain.
²⁴ Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Spain.
²⁵ NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health, Oslo, Norway.
²⁶ Université Paris Cité, EA4468, Maladie d'Alzheimer, F-75013 Paris, France.
²⁷ The Research-Centre for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway.
²⁸ Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
²⁹ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
³⁰ Department of Neurology, UMC Utrecht Brain Center, Utrecht, The Netherlands.
³¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
³² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³³ Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France.
³⁴ German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.
³⁵ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
³⁶ Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
³⁷ Fundación Pública Galega de Medicina Xenómica-CIBERER-IDIS, Santiago de Compostela, Spain.
³⁸ Department of Neurology, CHU de Bordeaux, 33000, Bordeaux, France.
³⁹ Radboudumc Alzheimer Center, Department of Geriatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴⁰ Donders Center for Medical Neuroscience, Nijmegen, The Netherlands.
⁴¹ Department of Neurology, Boston University School of Medicine, Boston, MA, 2115, USA.
⁴² Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴³ Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
⁴⁴ kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany.
⁴⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁴⁶ Department of Clinical Science, NORMENT Centre, University of Bergen, Bergen, Norway.
⁴⁷ Pôle de Santé Publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
⁴⁸ Univerisité Paris-Saclay. Inserm 1178 MOODS, Paris, France.
⁴⁹ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
⁵⁰ Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany.
⁵¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵² Department of Neurology, Akershus University Hospital, Lorenskog, Norway.
⁵³ Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg, Germany.
⁵⁴ Cognitive Impairment Unit, Neurology Service, "Marqués de Valdecilla" University Hospital, Institute for Research "Marques de Valdecilla" (IDIVAL), University of Cantabria, Santander, Spain, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
⁵⁵ Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
⁵⁶ A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
⁵⁷ Alzheimer Precision Medicine (APM), Sorbonne University, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
⁵⁸ Neurology Business Group, Eisai Inc, 100 Tice Blvd, Woodcliff Lake, NJ, 07677, USA.
⁵⁹ Service gériatrie, Centre Mémoire de Ressources et Recherches Ile de France-Broca, AP-HP, Hôpital Broca, F-75013, Paris, France.
⁶⁰ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, 53127, Bonn, Germany.
⁶¹ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
⁶² Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
⁶³ Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden.
⁶⁴ Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
⁶⁵ Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
⁶⁶ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
⁶⁷ Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
⁶⁸ Bioinformatics Center, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
⁶⁹ Atlantic Fellow at the Global Brain Health Institute (GBHI) -, University of California, San Francisco, USA.
⁷⁰ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁷¹ Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
⁷² Institute of Clinical Medicine, Neurosurgery, University of Eastern Finland, Kuopio, Finland.
⁷³ Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
⁷⁴ Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland.
⁷⁵ Hospital Universitario Donostia-OSAKIDETZA, Donostia, Spain.
⁷⁶ Instituto Biodonostia, San Sebastián, Spain.
⁷⁷ University of The Basque Country, San Sebastian, Spain.
⁷⁸ Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁷⁹ Department of Genetics and CNR-MAJ, Normandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Rouen, France.
⁸⁰ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
⁸¹ Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany.
⁸² Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK.
⁸³ German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
⁸⁴ Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich and University of Zürich, Zurich, Switzerland.
⁸⁵ Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
⁸⁶ Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany.
⁸⁷ Department of Psychiatry and Psychotherapy, Klinikum rechts der isar, Technical University Munich, 81675, Munich, Germany.
⁸⁸ Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
⁸⁹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁹⁰ Department of Geriatrics, St Olav Hospital, University Hospital of Trondheim, Trondheim, Norway.
⁹¹ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, 28031, Madrid, Spain.
⁹² Department of Psychiatry and Psychotherapy, Medical Faculty, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁹³ Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany.
⁹⁴ German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
⁹⁵ Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany.
⁹⁶ 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece.
⁹⁷ Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁹⁸ Neurology, University Hospitals Leuven, Leuven, Belgium.
⁹⁹ Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium.
¹⁰⁰ Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, The Netherlands.
¹⁰¹ Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics Karolinska Institutet, Stockholm, Sweden.
¹⁰² Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Göttingen, Germany.
¹⁰³ Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
¹⁰⁴ Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Psychosis Clinic, Gothenburg, Sweden.
¹⁰⁵ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
¹⁰⁶ Medical Science Department, iBiMED, Aveiro, Portugal.
¹⁰⁷ Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
¹⁰⁸ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
¹⁰⁹ UK Dementia Research Institute at UCL, London, UK.
¹¹⁰ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹¹¹ Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
¹¹² Nuffield Department of Population Health, Oxford University, Oxford, UK.
¹¹³ Laboratory of Neurochemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium.
¹¹⁴ Department of Neurology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
¹¹⁵ Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹¹⁶ Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹¹⁷ Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
¹¹⁸ 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.
¹¹⁹ Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
¹²⁰ Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
¹²¹ Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
¹²² Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
¹²³ Addiction, Oslo University Hospital, 0407, Oslo, Norway.
¹²⁴ Department of Psychiatry, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
¹²⁵ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands. wm.vdflier@amsterdamumc.nl.
¹²⁶ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands. wm.vdflier@amsterdamumc.nl.

^# Contributed equally.

PMID: 36066633
PMCID: PMC9547780
DOI: 10.1007/s00401-022-02454-z

Meta-Analysis

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Iris E Jansen et al. Acta Neuropathol. 2022 Nov.

. 2022 Nov;144(5):821-842.

doi: 10.1007/s00401-022-02454-z. Epub 2022 Sep 6.

Authors

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands. i.e.jansen@vu.nl.
² Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands. i.e.jansen@vu.nl.
³ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, The Netherlands. i.e.jansen@vu.nl.
⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.
⁵ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
⁶ Section Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.
⁷ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁸ NeuroGenomics and Informatics, Washington University School of Medicine, St Louis, MO, USA.
⁹ Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.
¹⁰ Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
¹¹ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
¹² Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³ Neurosciences and Complex Systems Unit (ENyS), CONICET, Hospital El Cruce, National University A. Jauretche (UNAJ), Florencio Varela, Argentina.
¹⁴ Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE / Labex DISTALZ - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000, Lille, France.
¹⁵ Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden.
¹⁶ University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, 33000, Bordeaux, France.
¹⁷ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany.
¹⁸ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁹ Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
²⁰ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
²¹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, The Netherlands.
²² Sant Pau Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
²³ Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain.
²⁴ Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Spain.
²⁵ NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health, Oslo, Norway.
²⁶ Université Paris Cité, EA4468, Maladie d'Alzheimer, F-75013 Paris, France.
²⁷ The Research-Centre for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway.
²⁸ Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
²⁹ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
³⁰ Department of Neurology, UMC Utrecht Brain Center, Utrecht, The Netherlands.
³¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
³² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³³ Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France.
³⁴ German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.
³⁵ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
³⁶ Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
³⁷ Fundación Pública Galega de Medicina Xenómica-CIBERER-IDIS, Santiago de Compostela, Spain.
³⁸ Department of Neurology, CHU de Bordeaux, 33000, Bordeaux, France.
³⁹ Radboudumc Alzheimer Center, Department of Geriatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴⁰ Donders Center for Medical Neuroscience, Nijmegen, The Netherlands.
⁴¹ Department of Neurology, Boston University School of Medicine, Boston, MA, 2115, USA.
⁴² Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴³ Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
⁴⁴ kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany.
⁴⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁴⁶ Department of Clinical Science, NORMENT Centre, University of Bergen, Bergen, Norway.
⁴⁷ Pôle de Santé Publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
⁴⁸ Univerisité Paris-Saclay. Inserm 1178 MOODS, Paris, France.
⁴⁹ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
⁵⁰ Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany.
⁵¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵² Department of Neurology, Akershus University Hospital, Lorenskog, Norway.
⁵³ Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg, Germany.
⁵⁴ Cognitive Impairment Unit, Neurology Service, "Marqués de Valdecilla" University Hospital, Institute for Research "Marques de Valdecilla" (IDIVAL), University of Cantabria, Santander, Spain, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
⁵⁵ Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
⁵⁶ A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
⁵⁷ Alzheimer Precision Medicine (APM), Sorbonne University, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
⁵⁸ Neurology Business Group, Eisai Inc, 100 Tice Blvd, Woodcliff Lake, NJ, 07677, USA.
⁵⁹ Service gériatrie, Centre Mémoire de Ressources et Recherches Ile de France-Broca, AP-HP, Hôpital Broca, F-75013, Paris, France.
⁶⁰ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, 53127, Bonn, Germany.
⁶¹ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
⁶² Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
⁶³ Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden.
⁶⁴ Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
⁶⁵ Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
⁶⁶ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
⁶⁷ Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
⁶⁸ Bioinformatics Center, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
⁶⁹ Atlantic Fellow at the Global Brain Health Institute (GBHI) -, University of California, San Francisco, USA.
⁷⁰ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁷¹ Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
⁷² Institute of Clinical Medicine, Neurosurgery, University of Eastern Finland, Kuopio, Finland.
⁷³ Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
⁷⁴ Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland.
⁷⁵ Hospital Universitario Donostia-OSAKIDETZA, Donostia, Spain.
⁷⁶ Instituto Biodonostia, San Sebastián, Spain.
⁷⁷ University of The Basque Country, San Sebastian, Spain.
⁷⁸ Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁷⁹ Department of Genetics and CNR-MAJ, Normandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Rouen, France.
⁸⁰ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
⁸¹ Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany.
⁸² Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK.
⁸³ German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
⁸⁴ Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich and University of Zürich, Zurich, Switzerland.
⁸⁵ Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
⁸⁶ Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany.
⁸⁷ Department of Psychiatry and Psychotherapy, Klinikum rechts der isar, Technical University Munich, 81675, Munich, Germany.
⁸⁸ Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
⁸⁹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁹⁰ Department of Geriatrics, St Olav Hospital, University Hospital of Trondheim, Trondheim, Norway.
⁹¹ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, 28031, Madrid, Spain.
⁹² Department of Psychiatry and Psychotherapy, Medical Faculty, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁹³ Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany.
⁹⁴ German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
⁹⁵ Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany.
⁹⁶ 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece.
⁹⁷ Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁹⁸ Neurology, University Hospitals Leuven, Leuven, Belgium.
⁹⁹ Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium.
¹⁰⁰ Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, The Netherlands.
¹⁰¹ Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics Karolinska Institutet, Stockholm, Sweden.
¹⁰² Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Göttingen, Germany.
¹⁰³ Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
¹⁰⁴ Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Psychosis Clinic, Gothenburg, Sweden.
¹⁰⁵ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
¹⁰⁶ Medical Science Department, iBiMED, Aveiro, Portugal.
¹⁰⁷ Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
¹⁰⁸ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
¹⁰⁹ UK Dementia Research Institute at UCL, London, UK.
¹¹⁰ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹¹¹ Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
¹¹² Nuffield Department of Population Health, Oxford University, Oxford, UK.
¹¹³ Laboratory of Neurochemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium.
¹¹⁴ Department of Neurology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
¹¹⁵ Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹¹⁶ Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹¹⁷ Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
¹¹⁸ 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.
¹¹⁹ Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
¹²⁰ Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
¹²¹ Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
¹²² Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
¹²³ Addiction, Oslo University Hospital, 0407, Oslo, Norway.
¹²⁴ Department of Psychiatry, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
¹²⁵ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands. wm.vdflier@amsterdamumc.nl.
¹²⁶ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands. wm.vdflier@amsterdamumc.nl.

^# Contributed equally.

PMID: 36066633
PMCID: PMC9547780
DOI: 10.1007/s00401-022-02454-z

Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Keywords: Alzheimer’s disease; Amyloid-beta; Cerebrospinal fluid; GWAS; Tau.

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Conflict of interest statement

Research programs of Wiesje van der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health ~ Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Biogen MA Inc, Boehringer Ingelheim, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health ~ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF has performed contract research for Biogen MA Inc, and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare. WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. WF participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. CC receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics and ADx Healthcare. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KBlennow has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OAA is a consultant to HealthLytix, and received speaker’s honorarium from Lundbeck and Sunovion. SE has served at scientific advisory boards for Biogen, Danone, Eisai, icometrix, Pfizer, Novartis, Nutricia, Roche and has received unrestricted research grants from ADx Neurosciences and Janssen Pharmaceutica. CC receives research support from: Biogen, EISAI, Alector, GSK and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics and ADx Healthcare. HHampel is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; during the past three years he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. DA participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. OG reports consulting fees from Eli Lilly, grants to his institution from Actelion, and prescreening activities for Julius Clinical/Toyama. ABK has been a PI in the drug trials Roche BN29553, Boehringer-Ingelheim 1346.0023 and is PI in Novo Nordisk NN6535-4730. AL has received personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia,Krka Farmacéutica SL, Biogen and Zambon. PSJ has received personal fees for advisory board from Roche Diagnostics and Zambon. GS participated in one advisory board meeting from Biogen. MI is a paid consultant to BioArctic AB. KS is editor at Acta Neuropathologica and associate editor at Alzheimer’s Research & Therapy. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). All other authors declare no financial interests or potential conflicts of interest.

Figures

**Fig. 1**
Manhattan plots of the stage 3 GWAS results. a Results visualized for CSFAβ42; b Results visualized for CSF pTau. The y-axes are limited to visualize the non-APOE loci. The lowest P values for APOE are 4.07 × 10^–355 and 3.74 × 10^–94 for Aβ42 and pTau, respectively

**Fig. 2**
LocusZoom plots showing variant association results for a *GMNC* and b *C16orf9*5 loci. In black, the pTau association signals of this study; and in orange, the lateral ventricular volume (LVV) association signals observed in other studies

**Fig. 3**
The effects of all AD-associated loci. The names of the loci are named according to their linked gene names in Bellinguez et al. (2021). Hierarchical clustering was performed on the rows and columns using Eucledian distances and the method ‘average’ for clustering Pathway enrichment analyses was performed on the four first clusters. The enrichment analyses are in Online Resource 1—Table 9. The upper bar shows the odds ratio for AD, where alleles for variants with protective effects have been flipped to show AD-risk increasing effects for all variants. The increases in Aβ42 and pTau (positive Zscores) are shown in red and decreases in AB42 and PTau (negative Z scores) are shown in blue. * = P value < 0.05, X = 0.05 < P value < 0.001, # = 0.001 < P value < 5 × 10^–8, $ = P value < 5 × 10^–8

See this image and copyright information in PMC

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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

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