Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Author:

Le Guen Yann12,Belloy Michael E.1,Grenier-Boley Benjamin3,de Rojas Itziar45,Castillo-Morales Atahualpa6,Jansen Iris78,Nicolas Aude3,Bellenguez Céline3,Dalmasso Carolina910,Küçükali Fahri111213,Eger Sarah J.1,Rasmussen Katrine Laura1415,Thomassen Jesper Qvist14,Deleuze Jean-François16,He Zihuai117,Napolioni Valerio18,Amouyel Philippe3,Jessen Frank91920,Kehoe Patrick G.21,van Duijn Cornelia2223,Tsolaki Magda24,Sánchez-Juan Pascual525,Sleegers Kristel111213,Ingelsson Martin262728,Rossi Giacomina29,Hiltunen Mikko30,Sims Rebecca31,van der Flier Wiesje M.7,Ramirez Alfredo919203233,Andreassen Ole A.3435,Frikke-Schmidt Ruth1415,Williams Julie631,Ruiz Agustín45,Lambert Jean-Charles3,Greicius Michael D.1,Arosio Beatrice36,Benussi Luisa37,Boland Anne16,Borroni Barbara38,Caffarra Paolo39,Daian Delphine16,Daniele Antonio4041,Debette Stéphanie4243,Dufouil Carole4445,Düzel Emrah4647,Galimberti Daniela4849,Giedraitis Vilmantas26,Grimmer Timo50,Graff Caroline51,Grünblatt Edna525354,Hanon Olivier55,Hausner Lucrezia56,Heilmann-Heimbach Stefanie57,Holstege Henne758,Hort Jakub5960,Jürgen Deckert61,Kuulasmaa Teemu30,van der Lugt Aad62,Masullo Carlo63,Mecocci Patrizia64,Mehrabian Shima65,de Mendonça Alexandre66,Moebus Susanne67,Nacmias Benedetta6869,Nicolas Gael70,Olaso Robert16,Papenberg Goran71,Parnetti Lucilla72,Pasquier Florence73,Peters Oliver7475,Pijnenburg Yolande A. L.7,Popp Julius767778,Rainero Innocenzo79,Ramakers Inez80,Riedel-Heller Steffi81,Scarmeas Nikolaos8283,Scheltens Philip7,Scherbaum Norbert84,Schneider Anja1932,Seripa Davide85,Soininen Hilkka86,Solfrizzi Vincenzo87,Spalletta Gianfranco8889,Squassina Alessio90,van Swieten John91,Tegos Thomas J.24,Tremolizzo Lucio92,Verhey Frans80,Vyhnalek Martin5960,Wiltfang Jens939495,Boada Mercè45,García-González Pablo45,Puerta Raquel4,Real Luis M.9697,Álvarez Victoria9899,Bullido María J.5100101,Clarimon Jordi5102,García-Alberca José María5103,Mir Pablo5104,Moreno Fermin5105106,Pastor Pau107108,Piñol-Ripoll Gerard109110,Molina-Porcel Laura111112,Pérez-Tur Jordi5113114,Rodríguez-Rodríguez Eloy5115,Royo Jose Luís97,Sánchez-Valle Raquel116,Dichgans Martin117118119,Rujescu Dan120,

Affiliation:

1. Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California

2. Institut du Cerveau, Paris Brain Institute, Paris, France

3. University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France

4. Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain

5. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

6. UKDRI@Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom

7. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands

8. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, Amsterdam, the Netherlands

9. Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

10. Estudios en Neurociencias y Sistemas Complejos (ENyS) CONICET-HEC-UNAJ, Universidad Nacional Arturo Jauretche, Florencio Varela, Argentina

11. Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

12. Laboratory of Neurogenetics, Born-Bunge Institute, Antwerp, Belgium

13. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

14. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

15. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

16. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France

17. Quantitative Sciences Unit, Department of Medicine, Stanford University, Palo Alto, California

18. School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

19. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

20. Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

21. Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom

22. Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands

23. Nuffield Department of Population Health Oxford University, Oxford, United Kingdom

24. 1st Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

25. Alzheimer’s Centre Reina Sofia-CIEN Foundation, Madrid, Spain

26. Department of Public Health and Caring Sciences / Geriatrics, Uppsala University, Uppsala, Sweden

27. Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada

28. Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada

29. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

30. Institute of Biomedicine, University of Eastern Finland, Joensuu, Kuopio, Finland

31. Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom

32. Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany

33. Department of Psychiatry and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, The University of Texas Health Science Center at San Antonio

34. NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

35. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

36. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

37. Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

38. Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

39. Unit of Neurology, University of Parma, Parma, Italy

40. Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy

41. Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

42. University Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France

43. Department of Neurology, Bordeaux University Hospital, Bordeaux, France

44. Inserm, Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, ISPED, CIC 1401-EC, Université de Bordeaux, Bordeaux, France

45. CHU de Bordeaux, Pole santé publique, Bordeaux, France

46. German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

47. Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany

48. Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda, Ospedale Policlinico, Milan, Italy

49. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

50. Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Psychiatry and Psychotherapy, Munich, Germany

51. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital-Solna, Stockholm, Sweden

52. Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland

53. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

54. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

55. Université de Paris, EA 4468, APHP, Hôpital Broca, Paris, France

56. Department of Geriatric Psychiatry, Central Institute of Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

57. Institute of Human Genetics, University of Bonn, School of Medicine, University Hospital Bonn, Bonn, Germany

58. Department of Clinical Genetics, VU University Medical Centre, Amsterdam, the Netherlands

59. Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic

60. International Clinical Research Center, St Anne’s University Hospital Brno, Brno, Czech Republic

61. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

62. Department of Radiology and Nuclear Medicine, ErasmusMC, Rotterdam, the Netherlands

63. Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy

64. Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy

65. Clinic of Neurology, UH Alexandrovska, Medical University Sofia, Sofia, Bulgaria

66. Faculty of Medicine, University of Lisbon, Lisbon, Portugal

67. Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany

68. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

69. IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy

70. Normandie Université, UNIROUEN, Inserm U1245 and CHU Rouen, Department of Genetics and CNR-MAJ, Rouen, France

71. Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden

72. Centre for Memory Disturbances, Lab of Clinical Neurochemistry, Section of Neurology, University of Perugia, Perugia, Italy

73. Université de Lille, Inserm 1172, CHU Clinical and Research Memory Research Centre (CMRR) of Distalz, Lille, France

74. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany

75. Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin, Germany

76. Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland

77. Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zurich, Switzerland

78. Institute for Regenerative Medicine, University of Zürich, Zurich, Switzerland

79. Department of Neuroscience “Rita Levi Montalcini,” University of Torino, Torino, Italy

80. Maastricht University, Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht, the Netherlands

81. Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany

82. 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece

83. 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

84. LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany

85. Laboratory for Advanced Hematological Diagnostics, Department of Hematology and Stem Cell Transplant, “Vito Fazzi” Hospital, Lecce, Italy

86. Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland

87. Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unit, University of Bari Aldo Moro, Bari, Italy

88. Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy

89. Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas

90. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

91. Department of Neurology, ErasmusMC, Rotterdam, the Netherlands

92. Neurology, “San Gerardo” Hospital, Monza and University of Milano-Bicocca, Milan, Italy

93. Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen, Germany

94. German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany

95. Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal

96. Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain

97. Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain

98. Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain

99. Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

100. Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid, Spain

101. Instituto de Investigacion Sanitaria ‘Hospital la Paz’ (IdIPaz), Madrid, Spain

102. Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

103. Alzheimer Research Center & Memory Clinic, Andalusian Institute for Neuroscience, Málaga, Spain

104. Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain

105. Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain

106. Neurosciences Area, Instituto Biodonostia, San Sebastian, Spain

107. Fundació Docència i Recerca MútuaTerrassa, Terrassa, Spain

108. Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain

109. Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain

110. Institut de Recerca Biomedica de Lleida (IRBLLeida), Lleida, Spain

111. Neurological Tissue Bank (Biobanc), Hospital Clinic IDIBAPS, Barcelona, Spain

112. Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clinic, Barcelona, Spain

113. Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain

114. Unidad Mixta de Neurologia Genètica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain

115. Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain

116. 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

117. Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany

118. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

119. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

120. Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria

Publisher

American Medical Association (AMA)

Subject

Neurology (clinical)

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