Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.,Nature Genetics

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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Nature Genetics ( IF 30.8 ) Pub Date : 2017-07-17 , DOI: 10.1038/ng.3916
Rebecca Sims ₁ , Sven J van der Lee ₂ , Adam C Naj ₃ , Céline Bellenguez _{4,

5,

6} , Nandini Badarinarayan ₁ , Johanna Jakobsdottir ₇ , Brian W Kunkle ₈ , Anne Boland ₉ , Rachel Raybould ₁ , Joshua C Bis ₁₀ , Eden R Martin _{8,

11} , Benjamin Grenier-Boley _{4,

5,

6} , Stefanie Heilmann-Heimbach _{12,

13} , Vincent Chouraki _{14,

15} , Amanda B Kuzma ₁₆ , Kristel Sleegers _{17,

18} , Maria Vronskaya ₁ , Agustin Ruiz ₁₉ , Robert R Graham ₂₀ , Robert Olaso ₉ , Per Hoffmann _{12,

13,

21} , Megan L Grove ₂₂ , Badri N Vardarajan _{23,

24,

25} , Mikko Hiltunen _{26,

27} , Markus M Nöthen _{12,

13} , Charles C White ₂₈ , Kara L Hamilton-Nelson ₈ , Jacques Epelbaum ₂₉ , Wolfgang Maier _{30,

31} , Seung-Hoan Choi _{14,

32} , Gary W Beecham _{8,

11} , Cécile Dulary ₉ , Stefan Herms _{12,

13,

21} , Albert V Smith _{7,

33} , Cory C Funk ₃₄ , Céline Derbois ₉ , Andreas J Forstner _{12,

13} , Shahzad Ahmad ₂ , Hongdong Li ₃₄ , Delphine Bacq ₉ , Denise Harold ₃₅ , Claudia L Satizabal _{14,

15} , Otto Valladares ₁₆ , Alessio Squassina ₃₆ , Rhodri Thomas ₁ , Jennifer A Brody ₁₀ , Liming Qu ₁₆ , Pascual Sánchez-Juan ₃₇ , Taniesha Morgan ₁ , Frank J Wolters ₂ , Yi Zhao ₁₆ , Florentino Sanchez Garcia ₃₈ , Nicola Denning ₁ , Myriam Fornage ₃₉ , John Malamon ₁₆ , Maria Candida Deniz Naranjo ₃₈ , Elisa Majounie ₁ , Thomas H Mosley ₄₀ , Beth Dombroski ₁₆ , David Wallon _{41,

42} , Michelle K Lupton _{43,

44} , Josée Dupuis ₃₂ , Patrice Whitehead ₈ , Laura Fratiglioni _{45,

46} , Christopher Medway ₄₇ , Xueqiu Jian ₃₉ , Shubhabrata Mukherjee ₄₈ , Lina Keller ₄₆ , Kristelle Brown ₄₇ , Honghuang Lin ₄₉ , Laura B Cantwell ₁₆ , Francesco Panza ₅₀ , Bernadette McGuinness ₅₁ , Sonia Moreno-Grau ₁₉ , Jeremy D Burgess ₅₂ , Vincenzo Solfrizzi ₅₃ , Petra Proitsi ₄₃ , Hieab H Adams ₂ , Mariet Allen ₅₂ , Davide Seripa ₅₄ , Pau Pastor ₅₅ , L Adrienne Cupples _{15,

32} , Nathan D Price ₃₄ , Didier Hannequin _{42,

56} , Ana Frank-García _{57,

58,

59} , Daniel Levy _{14,

15,

60} , Paramita Chakrabarty ₆₁ , Paolo Caffarra _{62,

63} , Ina Giegling ₆₄ , Alexa S Beiser _{15,

32} , Vilmantas Giedraitis ₆₅ , Harald Hampel _{66,

67,

68} , Melissa E Garcia ₆₉ , Xue Wang ₅₂ , Lars Lannfelt ₆₅ , Patrizia Mecocci ₅₅ , Gudny Eiriksdottir ₇ , Paul K Crane ₄₈ , Florence Pasquier _{70,

71} , Virginia Boccardi ₅₅ , Isabel Henández ₁₉ , Robert C Barber ₇₂ , Martin Scherer ₇₃ , Lluis Tarraga ₁₉ , Perrie M Adams ₇₄ , Markus Leber ₇₅ , Yuning Chen ₃₂ , Marilyn S Albert ₇₆ , Steffi Riedel-Heller ₇₇ , Valur Emilsson _{7,

78} , Duane Beekly ₇₉ , Anne Braae ₈₀ , Reinhold Schmidt ₈₁ , Deborah Blacker _{82,

83} , Carlo Masullo ₈₄ , Helena Schmidt ₈₅ , Rachelle S Doody ₈₆ , Gianfranco Spalletta ₈₇ , W T Longstreth _{88,

89} , Thomas J Fairchild ₉₀ , Paola Bossù ₈₇ , Oscar L Lopez _{91,

92} , Matthew P Frosch ₉₃ , Eleonora Sacchinelli ₈₇ , Bernardino Ghetti ₉₄ , Qiong Yang ₃₂ , Ryan M Huebinger ₉₅ , Frank Jessen _{30,

31,

75} , Shuo Li ₃₂ , M Ilyas Kamboh _{96,

97} , John Morris _{98,

99} , Oscar Sotolongo-Grau ₁₉ , Mindy J Katz ₁₀₀ , Chris Corcoran ₁₀₁ , Melanie Dunstan ₁ , Amy Braddel ₁ , Charlene Thomas ₁ , Alun Meggy ₁ , Rachel Marshall ₁ , Amy Gerrish ₁ , Jade Chapman ₁ , Miquel Aguilar _{102,

103} , Sarah Taylor ₁ , Matt Hill ₁ , Mònica Díez Fairén _{59,

102} , Angela Hodges ₁₀₄ , Bruno Vellas ₁₀₅ , Hilkka Soininen ₂₇ , Iwona Kloszewska ₁₀₆ , Makrina Daniilidou ₁₀₇ , James Uphill ₁₀₈ , Yogen Patel ₄₃ , Joseph T Hughes ₄₃ , Jenny Lord ₄₇ , James Turton ₄₇ , Annette M Hartmann ₆₄ , Roberta Cecchetti ₅₅ , Chiara Fenoglio ₁₀₉ , Maria Serpente ₁₀₉ , Marina Arcaro ₁₀₉ , Carlo Caltagirone ₈₇ , Maria Donata Orfei ₈₇ , Antonio Ciaramella ₈₇ , Sabrina Pichler ₁₁₀ , Manuel Mayhaus ₁₁₀ , Wei Gu ₁₁₀ , Alberto Lleó _{59,

111} , Juan Fortea _{59,

111} , Rafael Blesa _{59,

111} , Imelda S Barber ₈₀ , Keeley Brookes ₈₀ , Chiara Cupidi ₁₁₂ , Raffaele Giovanni Maletta ₁₁₂ , David Carrell ₁₁₃ , Sandro Sorbi _{114,

115} , Susanne Moebus ₁₁₆ , Maria Urbano ₅₄ , Alberto Pilotto ₅₄ , Johannes Kornhuber ₁₁₇ , Paolo Bosco ₁₁₈ , Stephen Todd ₅₁ , David Craig ₅₁ , Janet Johnston ₅₁ , Michael Gill ₁₁₉ , Brian Lawlor ₁₁₉ , Aoibhinn Lynch ₁₁₉ , Nick C Fox ₁₂₀ , John Hardy ₁₂₀ , , Roger L Albin _{121,

122,

123} , Liana G Apostolova _{124,

125,

126,

127} , Steven E Arnold ₁₂₈ , Sanjay Asthana _{129,

130,

131} , Craig S Atwood _{129,

130,

131} , Clinton T Baldwin ₁₃₂ , Lisa L Barnes _{133,

134,

135} , Sandra Barral _{23,

24,

25} , Thomas G Beach ₁₃₆ , James T Becker ₁₃₇ , Eileen H Bigio _{138,

139} , Thomas D Bird _{88,

140} , Bradley F Boeve ₁₄₁ , James D Bowen ₁₄₂ , Adam Boxer ₁₄₃ , James R Burke ₁₄₄ , Jeffrey M Burns ₁₄₅ , Joseph D Buxbaum _{146,

147,

148} , Nigel J Cairns ₁₄₉ , Chuanhai Cao ₁₅₀ , Chris S Carlson ₁₅₁ , Cynthia M Carlsson _{130,

131} , Regina M Carney ₁₅₂ , Minerva M Carrasquillo ₅₂ , Steven L Carroll ₁₅₃ , Carolina Ceballos Diaz ₆₁ , Helena C Chui ₁₅₄ , David G Clark _{155,

156} , David H Cribbs ₁₅₇ , Elizabeth A Crocco ₁₅₂ , Charles DeCarli ₁₅₈ , Malcolm Dick ₁₅₉ , Ranjan Duara ₁₆₀ , Denis A Evans ₁₆₁ , Kelley M Faber ₁₂₅ , Kenneth B Fallon ₁₆₂ , David W Fardo ₁₆₃ , Martin R Farlow ₁₂₆ , Steven Ferris ₁₆₄ , Tatiana M Foroud ₁₂₅ , Douglas R Galasko ₁₆₅ , Marla Gearing _{166,

167} , Daniel H Geschwind ₁₆₈ , John R Gilbert _{8,

11} , Neill R Graff-Radford _{52,

169} , Robert C Green ₁₇₀ , John H Growdon ₁₇₁ , Ronald L Hamilton ₁₇₂ , Lindy E Harrell ₁₇₃ , Lawrence S Honig ₂₃ , Matthew J Huentelman ₁₇₄ , Christine M Hulette ₁₇₅ , Bradley T Hyman ₁₇₁ , Gail P Jarvik _{176,

177} , Erin Abner ₁₇₈ , Lee-Way Jin ₁₇₉ , Gyungah Jun _{132,

180,

181} , Anna Karydas ₁₄₃ , Jeffrey A Kaye _{182,

183} , Ronald Kim ₁₈₄ , Neil W Kowall _{185,

186} , Joel H Kramer ₁₈₇ , Frank M LaFerla ₁₈₈ , James J Lah ₁₈₉ , James B Leverenz ₁₉₀ , Allan I Levey ₁₈₉ , Ge Li _{113,

140} , Andrew P Lieberman ₁₉₁ , Kathryn L Lunetta ₁₈₀ , Constantine G Lyketsos ₁₉₂ , Daniel C Marson ₁₇₃ , Frank Martiniuk ₁₉₃ , Deborah C Mash ₁₉₄ , Eliezer Masliah _{165,

195} , Wayne C McCormick ₄₈ , Susan M McCurry ₁₉₆ , Andrew N McDavid ₁₅₁ , Ann C McKee _{185,

186} , Marsel Mesulam _{139,

197} , Bruce L Miller ₁₄₃ , Carol A Miller ₁₉₈ , Joshua W Miller ₁₇₉ , John C Morris _{149,

199} , Jill R Murrell _{94,

125} , Amanda J Myers ₁₅₂ , Sid O'Bryant ₂₀₀ , John M Olichney ₁₅₈ , Vernon S Pankratz ₂₀₁ , Joseph E Parisi ₂₀₂ , Henry L Paulson _{121,

123} , William Perry ₈ , Elaine Peskind ₁₁₃ , Aimee Pierce ₁₅₇ , Wayne W Poon ₁₅₉ , Huntington Potter ₂₀₃ , Joseph F Quinn _{182,

183} , Ashok Raj ₁₅₀ , Murray Raskind ₁₁₃ , Barry Reisberg _{164,

204} , Christiane Reitz _{24,

25,

205} , John M Ringman ₂₀₆ , Erik D Roberson ₁₇₃ , Ekaterina Rogaeva ₂₀₇ , Howard J Rosen ₁₄₃ , Roger N Rosenberg ₂₀₈ , Mark A Sager ₁₃₀ , Andrew J Saykin _{125,

127} , Julie A Schneider _{133,

135,

209} , Lon S Schneider _{154,

210} , William W Seeley ₁₄₃ , Amanda G Smith ₁₅₀ , Joshua A Sonnen ₂₁₁ , Salvatore Spina ₉₄ , Robert A Stern ₁₈₅ , Russell H Swerdlow ₁₄₅ , Rudolph E Tanzi ₁₇₁ , Tricia A Thornton-Wells ₂₁₂ , John Q Trojanowski ₂₁₃ , Juan C Troncoso ₂₁₄ , Vivianna M Van Deerlin ₂₁₃ , Linda J Van Eldik ₂₁₅ , Harry V Vinters _{206,

216} , Jean Paul Vonsattel ₂₁₇ , Sandra Weintraub _{139,

218} , Kathleen A Welsh-Bohmer _{144,

219} , Kirk C Wilhelmsen ₂₂₀ , Jennifer Williamson ₂₃ , Thomas S Wingo ₁₈₉ , Randall L Woltjer ₂₂₁ , Clinton B Wright ₂₂₂ , Chang-En Yu ₄₈ , Lei Yu _{133,

135} , Fabienne Garzia ₉ , Feroze Golamaully ₉ , Gislain Septier ₉ , Sebastien Engelborghs _{18,

223} , Rik Vandenberghe _{223,

224} , Peter P De Deyn _{18,

223} , Carmen Muñoz Fernadez ₃₈ , Yoland Aladro Benito ₃₈ , Hakan Thonberg _{225,

226} , Charlotte Forsell _{225,

226} , Lena Lilius _{225,

226} , Anne Kinhult-Stählbom _{225,

226} , Lena Kilander ₆₅ , RoseMarie Brundin ₆₅ , Letizia Concari _{62,

63} , Seppo Helisalmi _{27,

227} , Anne Maria Koivisto _{27,

227} , Annakaisa Haapasalo _{27,

227} , Vincent Dermecourt ₂₂₈ , Nathalie Fievet _{4,

5,

6,

229} , Olivier Hanon ₂₂₉ , Carole Dufouil _{230,

231} , Alexis Brice _{232,

233} , Karen Ritchie ₂₃₄ , Bruno Dubois _{235,

236,

237,

238} , Jayanadra J Himali ₁₄ , C Dirk Keene ₂₁₁ , JoAnn Tschanz ₁₀₁ , Annette L Fitzpatrick _{89,

239} , Walter A Kukull ₈₉ , Maria Norton ₁₀₁ , Thor Aspelund _{7,

240} , Eric B Larson _{48,

241} , Ron Munger ₁₀₁ , Jerome I Rotter ₂₄₂ , Richard B Lipton ₁₀₀ , María J Bullido _{58,

59,

243} , Albert Hofman ₂ , Thomas J Montine ₂₁₁ , Eliecer Coto ₂₄₄ , Eric Boerwinkle _{22,

245} , Ronald C Petersen ₁₄₁ , Victoria Alvarez ₂₄₄ , Fernando Rivadeneira _{2,

246,

247} , Eric M Reiman _{174,

248,

249,

250} , Maura Gallo ₁₁₂ , Christopher J O'Donnell ₁₅ , Joan S Reisch ₂₅₁ , Amalia Cecilia Bruni ₁₁₂ , Donald R Royall ₂₅₂ , Martin Dichgans _{253,

254} , Mary Sano ₁₄₈ , Daniela Galimberti ₁₀₉ , Peter St George-Hyslop _{207,

255} , Elio Scarpini ₁₀₉ , Debby W Tsuang _{113,

140} , Michelangelo Mancuso ₂₅₆ , Ubaldo Bonuccelli ₂₅₆ , Ashley R Winslow ₂₅₇ , Antonio Daniele ₂₅₈ , Chuang-Kuo Wu ₂₅₉ , , Oliver Peters ₂₆₀ , Benedetta Nacmias _{114,

115} , Matthias Riemenschneider ₁₁₀ , Reinhard Heun ₃₁ , Carol Brayne ₂₆₁ , David C Rubinsztein ₂₅₅ , Jose Bras _{120,

262} , Rita Guerreiro _{120,

262} , Ammar Al-Chalabi ₂₆₃ , Christopher E Shaw ₂₆₃ , John Collinge ₁₀₈ , David Mann ₂₆₄ , Magda Tsolaki ₂₆₅ , Jordi Clarimón _{59,

111} , Rebecca Sussams ₂₆₆ , Simon Lovestone ₂₆₇ , Michael C O'Donovan ₁ , Michael J Owen ₁ , Timothy W Behrens ₂₀ , Simon Mead ₁₀₈ , Alison M Goate ₁₄₇ , Andre G Uitterlinden _{2,

108,

109} , Clive Holmes ₁₄₀ , Carlos Cruchaga _{98,

99} , Martin Ingelsson ₆₅ , David A Bennett _{133,

135} , John Powell ₄₃ , Todd E Golde _{61,

268} , Caroline Graff _{45,

226} , Philip L De Jager ₂₆₉ , Kevin Morgan ₄₇ , Nilufer Ertekin-Taner _{52,

169} , Onofre Combarros ₃₇ , Bruce M Psaty _{10,

59,

89,

270} , Peter Passmore ₅₁ , Steven G Younkin _{52,

169} , Claudine Berr _{235,

271,

272} , Vilmundur Gudnason _{7,

33} , Dan Rujescu ₆₄ , Dennis W Dickson ₅₂ , Jean-François Dartigues ₂₇₃ , Anita L DeStefano _{15,

32} , Sara Ortega-Cubero _{59,

274,

275} , Hakon Hakonarson ₂₇₆ , Dominique Campion _{41,

42} , Merce Boada ₁₉ , John Keoni Kauwe ₂₇₇ , Lindsay A Farrer _{14,

132,

180,

181,

185} , Christine Van Broeckhoven _{17,

18} , M Arfan Ikram _{2,

278} , Lesley Jones ₁ , Jonathan L Haines ₂₇₉ , Christophe Tzourio _{232,

280} , Lenore J Launer ₆₉ , Valentina Escott-Price ₁ , Richard Mayeux _{23,

24,

25} , Jean-François Deleuze ₉ , Najaf Amin ₂ , Peter A Holmans ₁ , Margaret A Pericak-Vance _{8,

11} , Philippe Amouyel _{4,

5,

6,

70} , Cornelia M van Duijn ₂ , Alfredo Ramirez _{12,

31,

75} , Li-San Wang ₁₆ , Jean-Charles Lambert _{4,

5,

6} , Sudha Seshadri _{14,

15} , Julie Williams ₁ , Gerard D Schellenberg ₁₆

Affiliation

Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
INSERM, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.
Institut Pasteur de Lille, Lille, France.
University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France.
Icelandic Heart Association, Kopavogur, Iceland.
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
CEA/Institut de Génomique, Centre National de Génotypage, Evry, France.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida, USA.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
Boston University School of Medicine, Boston, Massachusetts, USA.
Framingham Heart Study, Framingham, Massachusetts, USA.
Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
Immunology Biomarkers Group, Genentech, South San Francisco, California, USA.
Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, USA.
Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.
Department of Neurology, Columbia University, New York, New York, USA.
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
UMR 894, Center for Psychiatry and Neuroscience, INSERM, Université Paris Descartes, Paris, France.
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Institute for Systems Biology, Seattle, Washington, USA.
School of Biotechnology, Dublin City University, Dublin, Ireland.
Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Neurology Service and CIBERNED, 'Marqués de Valdecilla' University Hospital (University of Cantabria and IFIMAV), Santander, Spain.
Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain.
Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Centre Hospitalier du Rouvray, Sotteville les Rouen, France.
INSERM U1079, Rouen University, IRIB, Normandy University, Rouen, France.
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Department of Medicine, University of Washington, Seattle, Washington, USA.
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK.
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy.
Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.
Department of Neurology, Rouen University Hospital, Rouen, France.
Department of Neurology, University Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
Instituto de Investigación Sanitaria Hospital la Paz (IdiPAZ), Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
Department of Neuroscience, University of Parma, Parma, Italy.
Center for Cognitive Disorders AUSL, Parma, Italy.
Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany.
Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
AXA Research Fund and UPMC Chair, Paris, France.
Sorbonne Universités, Université Pierre et Marie Curie, Paris, France.
Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) and Institut du Cerveau et de la Moelle Épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.
Centre Hospitalier Universitaire de Lille, Epidemiology and Public Health Department, Lille, France.
INSERM UMRS 1171, CNR-Maj, Lille, France.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Department of Primary Medical Care, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.
Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, UK.
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria.
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
Department of Neurology, Catholic University of Rome, Rome, Italy.
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, USA.
Experimental Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Rome, Italy.
Department of Neurology, University of Washington, Seattle, Washington, USA.
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
Office of Strategy and Measurement, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
Department of Mathematics and Statistics, Utah State University, Logan, Utah, USA.
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain.
Memory Unit, Department of Neurology, Hospital Universitario Mútua Terrassa, Terrassa, Barcelona, Spain.
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
INSERM U558, University of Toulouse, Toulouse, France.
Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland.
Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, Leicester, UK.
Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany.
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
NEUROFARBA (Department of Neuroscience, Psychology, Drug Research and Child Health), University of Florence, Florence, Italy.
IRCCS 'Don Carlo Gnocchi', Florence, Italy.
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany.
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima Srl, Troina, Italy.
Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland.
Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK.
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, USA.
Michigan Alzheimer Disease Center, Ann Arbor, Michigan, USA.
Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA.
Department of Neurology, Indiana University, Indianapolis, Indiana, USA.
Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, USA.
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, Wisconsin, USA.
Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, USA.
Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, USA.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA.
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, USA.
Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
VA Puget Sound Health Care System/GRECC, Seattle, Washington, USA.
Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
Swedish Medical Center, Seattle, Washington, USA.
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Department of Medicine, Duke University, Durham, North Carolina, USA.
University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA.
USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Neurology, University of Southern California, Los Angeles, California, USA.
Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Neurology, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA.
Department of Neurology, University of California, Irvine, Irvine, California, USA.
Department of Neurology, University of California, Davis, Sacramento, California, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California, USA.
Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, USA.
Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Sanders-Brown Center on Aging, Department of Biostatistics, University of Kentucky, Lexington, Kentucky, USA.
Department of Psychiatry, New York University, New York, New York, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, USA.
Neurogenetics Program, University of California, Los Angeles, Los Angeles, California, USA.
Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.
Department of Pathology, Duke University, Durham, North Carolina, USA.
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA.
Sanders-Brown Center on Aging, College of Public Health, Department of Epidemiology, University of Kentucky, Lexington, Kentucky, USA.
Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California, USA.
Department of Biostatistics, Boston University, Boston, Massachusetts, USA.
Department of Ophthalmology, Boston University, Boston, Massachusetts, USA.
Department of Neurology, Oregon Health &Science University, Portland, Oregon, USA.
Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, California, USA.
Department of Neurology, Boston University, Boston, Massachusetts, USA.
Department of Pathology, Boston University, Boston, Massachusetts, USA.
Department of Neuropsychology, University of California, San Francisco, San Francisco, California, USA.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, USA.
Department of Neurology, Emory University, Atlanta, Georgia, USA.
Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Medicine-Pulmonary, New York University, New York, New York, USA.
Department of Neurology, University of Miami, Miami, Florida, USA.
Department of Pathology, University of California, San Diego, La Jolla, California, USA.
School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, USA.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Pathology, University of Southern California, Los Angeles, California, USA.
Department of Neurology, Washington University, St. Louis, Missouri, USA.
Internal Medicine, Division of Geriatrics, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Alzheimer's Disease Center, New York University, New York, New York, USA.
Department of Epidemiology, Columbia University, New York, New York, USA.
Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA.
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, USA.
Department of Psychiatry, University of Southern California, Los Angeles, California, USA.
Department of Pathology, University of Washington, Seattle, Washington, USA.
Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, USA.
Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Pathology, Oregon Health &Science University, Portland, Oregon, USA.
Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium.
Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven, Leuven, Belgium.
Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Department of Neurobiology, Care Sciences and Society, KIADRC, Karolinska Institutet, Stockholm, Sweden.
Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.
CHU Lille, Memory Center of Lille (Centre Mémoire de Ressources et de Recherche), Lille, France.
University Paris Descartes, EA 4468, AP-HP, Hôpital Broca, Geriatrics Department, Paris, France.
University of Bordeaux, Neuroepidemiology, Bordeaux, France.
INSERM, Neuroepidemiology, UMR 897, Bordeaux, France.
INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France.
AP-HP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France.
INSERM U1061, La Colombière Hospital, Montpellier, France.
Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
Institut des Neurosciences Translationnelles de Paris (IHU-A-ICM), Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.
INSERM, CNRS, UMRS 975, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.
Sorbonne Universités, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
Department of Family Medicine, University of Washington, Seattle, Washington, USA.
Centre for Public Health, University of Iceland, Reykjavik, Iceland.
Group Health Research Institute, Group Health, Seattle, Washington, USA.
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
Molecular Genetics Laboratory-Hospital, University of Central Asturias, Oviedo, Spain.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands.
Arizona Alzheimer's Consortium, Phoenix, Arizona, USA.
Banner Alzheimer's Institute, Phoenix, Arizona, USA.
Department of Psychiatry, University of Arizona, Phoenix, Arizona, USA.
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Departments of Psychiatry, Medicine, and Family and Community Medicine and South Texas Veterans Health Administration Geriatric Research Education and Clinical Center (GRECC), University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
Institute of Neurology, Catholic University of Sacred Hearth, Rome, Italy.
Departments of Neurology, Pharmacology, and Neuroscience, Texas Tech University Health Science Center, Lubbock, Texas, USA.
Department of Psychiatry, Charité University Medicine, Berlin, Germany.
Institute of Public Health, University of Cambridge, Cambridge, UK.
Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neuroscience Research Group, University of Manchester, Manchester, UK.
3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.
Department of Psychiatry, University of Oxford, Oxford, UK.
Florida Alzheimer's Disease Research Center, Gainesville, Florida, USA.
Center for Translational and Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA.
Department of Health Services, University of Washington, Seattle, Washington, USA.
Memory Research and Resources Center, CMRR of Montpellier, Department of Neurology, Hospital Gui de Chauliac, Montpellier, France.
Department of Neurology, Montpellier University, Montpellier, France.
Memory Research and Resources Center, CMRR de Bordeaux, Bordeaux, France.
Neurogenetics Laboratory, Division of Neurosciences, Centre for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain.
Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain.
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Departments of Biology and Neuroscience, Brigham Young University, Provo, Utah, USA.
Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
University of Bordeaux, Neuroepidemiology, UMR 897, Bordeaux, France.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

中文翻译：

PLCG2、ABI3 和 TREM2 中的罕见编码变异表明阿尔茨海默病中小胶质细胞介导的先天免疫。

我们在对 85,133 名受试者进行的三阶段病例对照研究中发现了与阿尔茨海默病相关的罕见编码变异。在第 1 阶段，我们使用全外显子组微阵列对 34,174 个样本进行了基因分型。在第 2 阶段，我们使用从头基因分型和估算基因型在 35,962 个独立样本中测试了相关变异 (P < 1 × 10-4)。在第 3 阶段，我们使用额外的 14,997 个样本来使用推算基因型测试最重要的第 2 阶段关联 (P < 5 × 10-8)。我们观察到三个与阿尔茨海默病相关的新的全基因组显着非同义变异：PLCG2 中的一个保护性变异（rs72824905：p.Pro522Arg，P = 5.38 × 10-10，优势比（OR）= 0.68，次要等位基因频率（MAF）病例= 0.0059，MAFcontrols = 0.0093），ABI3 中的风险变异（rs616338：p.Ser209Phe，P = 4.56 × 10-10，OR = 1.43，MAFcases = 0.011，MAFcontrols = 0.008)，以及 TREM2 中一个新的全基因组显着变异（rs143332484：p.Arg62His，P = 1.55 × 10-14，OR = 1.67，MAFcases = 0.0143，MAFcontrols = 0.0089），已知的阿尔茨海默病易感基因. 这些改变蛋白质的变化发生在小胶质细胞中高度表达的基因中，并突出了一个免疫相关的蛋白质-蛋白质相互作用网络，该网络富含先前发现的阿尔茨海默病风险基因。这些遗传学发现提供了额外的证据，证明小胶质细胞介导的先天免疫反应直接导致阿尔茨海默氏病的发展。这些改变蛋白质的变化发生在小胶质细胞中高度表达的基因中，并突出了一个免疫相关的蛋白质-蛋白质相互作用网络，该网络富含先前发现的阿尔茨海默病风险基因。这些遗传学发现提供了额外的证据，证明小胶质细胞介导的先天免疫反应直接导致阿尔茨海默氏病的发展。这些改变蛋白质的变化发生在小胶质细胞中高度表达的基因中，并突出了一个免疫相关的蛋白质-蛋白质相互作用网络，该网络富含先前发现的阿尔茨海默病风险基因。这些遗传学发现提供了额外的证据，证明小胶质细胞介导的先天免疫反应直接导致阿尔茨海默氏病的发展。

更新日期：2017-08-31

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