New insights on the genetic etiology of Alzheimer’s and related dementia
Authors: Bellenguez Céline , Küçükali Fahri , Jansen Iris , Andrade Victor , Moreno-Grau Sonia , Amin Najaf , Naj Adam C. , Grenier-Boley Benjamin , Campos-Martin Rafael , Holmans Peter A. , Boland Anne , Kleineidam Luca , Damotte Vincent , van der Lee Sven J. , Kuulasmaa Teemu , Yang Qiong , de Rojas Itziar , Bis Joshua C. , Yaqub Amber , Prokic Ivana , Costa Marcos R , Chapuis Julien , Ahmad Shahzad , Giedraitis Vilmantas , Boada Mercè , Aarsland Dag , García-González Pablo , Abdelnour Carla , Alarcón-Martín Emilio , Alegret Montserrat , Alvarez Ignacio , Álvarez Victoria , Armstrong Nicola J. , Tsolaki Anthoula , Antúnez Carmen , Appollonio Ildebrando , Arcaro Marina , Archetti Silvana , Pastor Alfonso Arias , Arosio Beatrice , Athanasiu Lavinia , Bailly Henri , Banaj Nerisa , Baquero Miquel , Belén Pastor Ana , Benussi Luisa , Berr Claudine , Besse Céline , Bessi Valentina , Binetti Giuliano , Bizzarro Alessandra , Alcolea Daniel , Blesa Rafael , Borroni Barbara , Boschi Silvia , Bossù Paola , Bråthen Geir , Bresner Catherine , Brookes Keeley J. , Brusco Luis Ignacio , Bûrger Katharina , Bullido María J. , Burholt Vanessa , Bush William S. , Calero Miguel , Dufouil Carole , Carracedo Ángel , Cecchetti Roberta , Cervera-Carles Laura , Charbonnier Camille , Chillotti Caterina , Brodaty Henry , Ciccone Simona , Claassen Jurgen A.H.R. , Clark Christopher , Conti Elisa , Corma-Gómez Anaïs , Costantini Emanuele , Custodero Carlo , Daian Delphine , Dalmasso Maria Carolina , Daniele Antonio , Dardiotis Efthimios , Dartigues Jean-François , de Deyn Peter Paul , de Paiva Lopes Katia , de Witte Lot D. , Debette Stéphanie , Deckert Jürgen , del Ser Teodoro , Denning Nicola , DeStefano Anita , Dichgans Martin , Diehl-Schmid Janine , Diez-Fairen Mónica , Rossi Paolo Dionigi , Djurovic Srdjan , Duron Emmanuelle , Düzel Emrah , Engelborghs Sebastiaan , Escott-Price Valentina , Espinosa Ana , Buiza-Rueda Dolores , Ewers Michael , Tagliavini Fabrizio , Nielsen Sune Fallgaard , Farotti Lucia , Fenoglio Chiara , Fernández-Fuertes Marta , Hardy John , Ferrari Raffaele , Ferreira Catarina B , Ferri Evelyn , Fin Bertrand , Fischer Peter , Fladby Tormod , Fließbach Klaus , Fortea Juan , Fostinelli Silvia , Fox Nick C. , Franco-Macías Emlio , Frank-García Ana , Froelich Lutz , Galimberti Daniela , García-Alberca Jose Maria , Garcia-Madrona Sebastian , García-Ribas Guillermo , Chene Geneviève , Ghidoni Roberta , Giegling Ina , Giaccone Giorgio , Goldhardt Oliver , González-Pérez Antonio , Graff Caroline , Grande Giulia , Green Emma , Grimmer Timo , Grünblatt Edna , Guetta-Baranes Tamar , Haapasalo Annakaisa , Hadjigeorgiou Georgios , Haines Jonathan L. , Hamilton-Nelson Kara L. ,   EADB,   Gra@ce,   ADGC,   Charge,   DemGen,   FinnGen,   EADI,   GERAD, Hampel Harald , Hanon Olivier , Hartmann Annette M. , Hausner Lucrezia , Harwood Janet , Heilmann-Heimbach Stefanie , Helisalmi Seppo , Heneka Michael T. , Hernández Isabel , Herrmann Martin J. , Hoffmann Per , Holmes Clive , Holstege Henne , Vilas Raquel Huerto , Hulsman Marc , Humphrey Jack , Biessels Geert Jan , Johansson Charlotte , Kehoe Patrick G. , Kilander Lena , Ståhlbom Anne Kinhult , Kivipelto Miia , Koivisto Anne , Kornhuber Johannes , Kosmidis Mary H. , Kuksa Pavel P. , Kunkle Brian W. , Lage Carmen , Laukka Erika J , Lauria Alessandra , Lee Chien-Yueh , Lehtisalo Jenni , Satizabal Claudia L. , Lerch Ondrej , Lleó Alberto , Lopez Rogelio , Lopez Oscar , de Munain Adolfo Lopez , Love Seth , Löwemark Malin , Luckcuck Lauren , Macías Juan , MacLeod Catherine A. , Maier Wolfgang , Mangialasche Francesca , Spallazzi Marco , Marquié Marta , Marshall Rachel , Martin Eden R. , Martín Montes Angel , Rodríguez Carmen Martínez , Masullo Carlo , Mayeux Richard , Mead Simon , Mecocci Patrizia , Medina Miguel , Meggy Alun , Mendoza Silvia , Menéndez-González Manuel , Mir Pablo , Periñán Maria Teresa , Mol Merel , Molina-Porcel Laura , Montrreal Laura , Morelli Laura , Moreno Fermín , Morgan Kevin , Nöthen Markus M. , Muchnik Carolina , Nacmias Benedetta , Ngandu Tiia , Nicolas Gael , Nordestgaard Børge G. , Olaso Robert , Orellana Adelina , Orsini Michela , Ortega Gemma , Padovani Alessandro , Caffarra Paolo , Papenberg Goran , Parnetti Lucilla , Pasquier Florence , Pastor Pau , Pérez-Cordón Alba , Pérez-Tur Jordi , Pericard Pierre , Peters Oliver , Pijnenburg Yolande A.L. , Pineda Juan A , Piñol-Ripoll Gerard , Pisanu Claudia , Polak Thomas , Popp Julius , Posthuma Danielle , Priller Josef , Puerta Raquel , Quenez Olivier , Quintela Inés , Thomassen Jesper Qvist , Rábano Alberto , Rainero Innocenzo , Ramakers Inez , Real Luis M , Reinders Marcel J.T. , Riedel-Heller Steffi , Riederer Peter , Rodriguez-Rodriguez Eloy , Rongve Arvid , Allende Irene Rosas , Rosende-Roca Maitée , Royo Jose Luis , Rubino Elisa , Rujescu Dan , Sáez María Eugenia , Sakka Paraskevi , Saltvedt Ingvild , Sanabria Ángela , Sánchez-Arjona María Bernal , Sanchez-Garcia Florentino , Mehrabian Shima , Sánchez-Juan Pascual , Sánchez-Valle Raquel , Sando Sigrid B , Scamosci Michela , Scarmeas Nikolaos , Scarpini Elio , Scheltens Philip , Scherbaum Norbert , Scherer Martin , Schmid Matthias , Schneider Anja , Schott Jonathan M. , Selbæk Geir , Sha Jin , Shadrin Alexey A , Skrobot Olivia , Snijders Gijsje J. L. , Soininen Hilkka , Solfrizzi Vincenzo , Solomon Alina , Sorbi Sandro , Sotolongo-Grau Oscar , Spalletta Gianfranco , Spottke Annika , Squassina Alessio , Tartari Juan Pablo , Tárraga Lluís , Tesí Niccolo , Thalamuthu Anbupalam , Tegos Thomas , Traykov Latchezar , Tremolizzo Lucio , Tybjærg-Hansen Anne , Uitterlinden Andre , Ullgren Abbe , Ulstein Ingun , Valero Sergi , Van Broeckhoven Christine , van der Lugt Aad , Van Dongen Jasper , van Rooij Jeroen , van Swieten John , Vandenberghe Rik , Verhey Frans , Vidal Jean-Sébastien , Vogelgsang Jonathan , Vyhnalek Martin , Wagner Michael , Wallon David , Wang Li-San , Wang Ruiqi , Weinhold Leonie , Wiltfang Jens , Windle Gill , Woods Bob , Yannakoulia Mary , Zhao Yi , Zulaica Miren , Serrano-Rios Manuel , Seripa Davide , Stordal Eystein , Farrer Lindsay A. , Psaty Bruce M. , Ghanbari Mohsen , Raj Towfique , Sachdev Perminder , Mather Karen , Jessen Frank , Ikram M. Arfan , de Mendonça Alexandre , Hort Jakub , Tsolaki Magda , Pericak-Vance Margaret A. , Amouyel Philippe , Williams Julie , Frikke-Schmidt Ruth , Clarimon Jordi , Deleuze Jean-François , Rossi Giacomina , Seshadri Sudha , Andreassen Ole A. , Ingelsson Martin , Hiltunen Mikko , Sleegers Kristel , Schellenberg Gerard D. , van Duijn Cornelia M. , Sims Rebecca , van der Flier Wiesje M. , Ruiz Agustín , Ramirez Alfredo , Lambert Jean-Charles 
Published: October 2020

ABSTRACTAlzheimer’s disease (AD) is a severe and incurable neurodegenerative disease, and the failure to find effective treatments suggests that the underlying pathology remains poorly understood. Due to its strong heritability, deciphering the genetic landscape of AD and related dementia (ADD) is a unique opportunity to advance our knowledge. We completed a meta-analysis of genome-wide association studies (39,106 clinically AD-diagnosed cases, 46,828 proxy-ADD cases and 401,577 controls) with the most promising signals followed-up in 25,392 independent AD cases and 276,086 controls. We report 75 risk loci for ADD, including 42 novel ones. Pathway-enrichment analyses confirm the involvement of amyloid/Tau pathways, highlight the role of microglia and its potential interaction with APP metabolism. Numerous genes exhibited differential expression or splicing in AD-related conditions and gene prioritization implies EGFR signaling and TNF-α pathway through LUBAC complex. We also generated a novel polygenic risk score strongly associated with the risk of future dementia or progression from mild cognitive impairment to dementia. In conclusion, by more than doubling the number of loci associated with ADD risk, our study offers new insights into the pathophysiological processes underlying AD and offers additional therapeutic entry-points and tools for translational genomics.