New insights into the genetic etiology of Alzheimer's disease and related dementias

Celine Bellenguez (1) , Fahri Kucukali , Iris E. Jansen , Luca Kleineidam , Sonia Moreno-Grau , Najaf Amin , Adam C. Naj , Rafael Campos-Martin , Benjamin Grenier-Boley (1) , Victor Andrade , Peter A. Holmans , Anne Boland (2) , Vincent Damotte , Sven J. van Der Lee , Marcos R. Costa , Teemu Kuulasmaa , Qiong Yang , Itziar de Rojas , Joshua C. Bis , Amber Yaqub , Ivana Prokic , Julien Chapuis (1) , Shahzad Ahmad , Vilmantas Giedraitis , Dag Aarsland , Pablo Garcia-Gonzalez , Carla Abdelnour , Emilio Alarcon-Martin , Daniel Alcolea , Montserrat Alegret , Ignacio Alvarez , Victoria Alvarez , Nicola J. Armstrong , Anthoula Tsolaki , Carmen Antunez , Ildebrando Appollonio , Marina Arcaro , Silvana Archetti , Alfonso Arias Pastor , Beatrice Arosio , Lavinia Athanasiu , Henri Bailly (3) , Nerisa Banaj , Miquel Baquero , Sandra Barral , Alexa Beiser , Ana Belen Pastor , Jennifer E. Below , Penelope Benchek , Luisa Benussi , Claudine Berr , Celine Besse (2) , Valentina Bessi , Giuliano Binetti , Alessandra Bizarro , Rafael Blesa , Merce Boada , Eric Boerwinkle , Barbara Borroni , Silvia Boschi , Paola Bossu , Geir Brathen , Jan Bressler , Catherine Bresner , Henry Brodaty , Keeley J. Brookes , Luis Ignacio Brusco , Dolores Buiza-Rueda , Katharina Burger , Vanessa Burholt , William S. Bush , Miguel Calero , Laura B. Cantwell , Genevieve Chene (4) , Jaeyoon Chung , Michael L. Cuccaro , Angel Carracedo , Roberta Cecchetti , Laura Cervera-Carles , Camille Charbonnier , Hung-Hsin Chen , Caterina Chillotti , Simona Ciccone , Jurgen A. H. R. Claassen , Christopher Clark , Elisa Conti , Anais Corma-Gomez , Emanuele Costantini , Carlo Custodero , Delphine Daian (2) , Maria Carolina Dalmasso , Antonio Daniele , Efthimios Dardiotis , Jean-Francois Dartigues (4) , Peter Paul de Deyn , Katia de Paiva Lopes , Lot D. de Witte , Stephanie Debette (4) , Jurgen Deckert , Teodoro del Ser , Nicola Denning , Anita Destefano , Martin Dichgans , Janine Diehl-Schmid , Monica Diez-Fairen , Paolo Dionigi Rossi , Srdjan Djurovic , Emmanuelle Duron (3) , Emrah Duzel , Carole Dufouil (4) , Gudny Eiriksdottir , Sebastiaan Engelborghs , Valentina Escott-Price , Ana Espinosa , Michael Ewers , Kelley M. Faber , Tagliavini Fabrizio , Sune Fallgaard Nielsen , David W. Fardo , Lucia Farotti , Chiara Fenoglio , Marta Fernandez-Fuertes , Raffaele Ferrari , Catarina B. Ferreira , Evelyn Ferri , Bertrand Fin (2) , Peter Fischer , Tormod Fladby , Klaus Fliessbach , Bernard Fongang , Myriam Fornage , Juan Fortea , Tatiana M. Foroud , Silvia Fostinelli , Nick C. Fox , Emlio Franco-Macias , Maria J. Bullido , Ana Frank-Garcia , Lutz Froelich , Brian Fulton-Howard , Daniela Galimberti , Jose Maria Garcia-Alberca , Sebastian Garcia-Madrona , Guillermo Garcia-Ribas , Roberta Ghidoni , Ina Giegling , Giaccone Giorgio , Alison M. Goate , Oliver Goldhardt , Duber Gomez-Fonseca , Antonio Gonzalez-Perez , Caroline Graff , Giulia Grande , Emma Green , Timo Grimmer , Edna Grunblatt , Michelle Grunin , Vilmundur Gudnason , Tamar Guetta-Baranes , Annakaisa Haapasalo , Georgios Hadjigeorgiou , Jonathan L. Haines , Kara L. Hamilton-Nelson , Harald Hampel (5) , Olivier Hanon (3) , John Hardy , Annette M. Hartmann , Lucrezia Hausner , Janet Harwood , Stefanie Heilmann-Heimbach , Seppo Helisalmi , Michael T. Heneka , Isabel Hernandez , Martin J. Herrmann , Per Hoffmann , Clive Holmes , Henne Holstege , Raquel Huerto Vilas , Marc Hulsman , Jack Humphrey , Geert Jan Biessels , Xueqiu Jian , Charlotte Johansson , Gyungah R. Jun , Yuriko Kastumata , John Kauwe , Patrick G. Kehoe , Lena Kilander , Anne Kinhult Stahlbom , Miia Kivipelto , Anne Koivisto , Johannes Kornhuber , Mary H. Kosmidis , Walter A. Kukull , Pavel P. Kuksa , Brian W. Kunkle , Amanda B. Kuzma , Carmen Lage , Erika J. Laukka , Lenore Launer , Alessandra Lauria , Chien-Yueh Lee , Jenni Lehtisalo , Ondrej Lerch , Alberto Lleo , William Jr Longstreth , Oscar Lopez , Adolfo Lopez de Munain , Seth Love , Malin Lowemark , Lauren Luckcuck , Kathryn L. Lunetta , Yiyi Ma , Juan Macias , Catherine A. Macleod , Wolfgang Maier , Francesca Mangialasche , Marco Spallazzi , Marta Marquie , Rachel Marshall , Eden R. Martin , Angel Martin Montes , Carmen Martinez Rodriguez , Carlo Masullo , Richard Mayeux , Simon Mead , Patrizia Mecocci , Miguel Medina , Alun Meggy , Shima Mehrabian , Silvia Mendoza , Manuel Menendez-Gonzalez , Pablo Mir , Susanne Moebus , Merel Mol , Laura Molina-Porcel , Laura Montrreal , Laura Morelli , Fermin Moreno , Kevin Morgan , Thomas Mosley , Markus M. Nothen , Carolina Muchnik , Shubhabrata Mukherjee , Benedetta Nacmias , Tiia Ngandu , Gael Nicolas , Borge G. Nordestgaard , Robert Olaso (2) , Adelina Orellana , Michela Orsini , Gemma Ortega , Alessandro Padovani , Caffarra Paolo , Goran Papenberg , Lucilla Parnetti , Florence Pasquier (6) , Pau Pastor , Gina Peloso , Alba Perez-Cordon , Jordi Perez-Tur , Pierre Pericard (7) , Oliver Peters , Yolande A. L. Pijnenburg , Juan A. Pineda , Gerard Pinol-Ripoll , Claudia Pisanu , Thomas Polak , Julius Popp , Danielle Posthuma , Josef Priller , Raquel Puerta , Olivier Quenez , Ines Quintela , Jesper Qvist Thomassen , Alberto Rabano , Innocenzo Rainero , Farid Rajabli , Inez Ramakers , Luis M. Real , Marcel J. T. Reinders , Christiane Reitz , Dolly Reyes-Dumeyer , Perry Ridge , Steffi Riedel-Heller , Peter Riederer , Natalia Roberto , Eloy Rodriguez-Rodriguez , Arvid Rongve , Irene Rosas Allende , Maitee Rosende-Roca , Jose Luis Royo , Elisa Rubino , Dan Rujescu , Maria Eugenia Saez , Paraskevi Sakka , Ingvild Saltvedt , Angela Sanabria , Maria Bernal Sanchez-Arjona , Florentino Sanchez-Garcia , Pascual Sanchez Juan , Raquel Sanchez-Valle , Sigrid B. Sando , Chloe Sarnowski , Claudia L. Satizabal , Michela Scamosci , Nikolaos Scarmeas , Elio Scarpini , Philip Scheltens , Norbert Scherbaum , Martin Scherer , Matthias Schmid , Anja Schneider , Jonathan M. Schott , Geir Selbaek , Davide Seripa , Manuel Serrano , Jin Sha , Alexey A. Shadrin , Olivia Skrobot , Susan Slifer , Gijsje J. L. Snijders , Hilkka Soininen , Vincenzo Solfrizzi , Alina Solomon , Yeunjoo Song , Sandro Sorbi , Oscar Sotolongo-Grau , Gianfranco Spalletta , Annika Spottke , Alessio Squassina , Eystein Stordal , Juan Pablo Tartan , Lluis Tarraga , Niccolo Tesi , Anbupalam Thalamuthu , Tegos Thomas , Giuseppe Tosto , Latchezar Traykov , Lucio Tremolizzo , Anne Tybjaerg-Hansen , Andre Uitterlinden , Abbe Ullgren , Ingun Ulstein , Sergi Valero , Otto Valladares , Christine Van Broeckhoven , Jeffery Vance , Badri N. Vardarajan , Aad van Der Lugt , Jasper Van Dongen , Jeroen van Rooij , John van Swieten , Rik Vandenberghe , Frans Verhey , Jean-Sebastien Vidal (3) , Jonathan Vogelgsang , Martin Vyhnalek , Michael Wagner (4) , David Wallon , Li-San Wang , Ruiqi Wang , Leonie Weinhold , Jens Wiltfang , Gill Windle , Bob Woods , Mary Yannakoulia , Habil Zare , Yi Zhao , Xiaoling Zhang , Congcong Zhu , Miren Zulaica , Lindsay A. Farrer , Bruce M. Psaty , Mohsen Ghanbari , Towfique Raj , Perminder Sachdev , Karen Mather , Frank Jessen , M. Arfan Ikram , Alexandre de Mendonca , Jakub Hort , Magda Tsolaki , Margaret A. Pericak-Vance , Philippe Amouyel (1) , Julie Williams , Ruth Frikke-Schmidt , Jordi Clarimon , Jean-Francois Deleuze , Giacomina Rossi , Sudha Seshadri , Ole A. Andreassen , Martin Ingelsson , Mikko Hiltunen , Kristel Sleegers , Gerard D. Schellenberg , Cornelia M. van Duijn , Rebecca Sims , Wiesje M. van Der Flier , Agustin Ruiz , Alfredo Ramirez , Jean-Charles Lambert (1)

1 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
2 CNRGH - Centre National de Recherche en Génomique Humaine
3 URP_4468 - Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologies
4 BPH - Bordeaux population health
5 GRC 21 - APM - Groupe de recherche clinique Alzheimer Precision Medicine
6 LilNCog - Lille Neurosciences & Cognition - U 1172
7 PLBS - Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Domaines: Santé publique et épidémiologie

Celine Bellenguez, Fahri Kucukali, Iris E. Jansen, Luca Kleineidam, Sonia Moreno-Grau, et al.. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature Genetics, 2022, 54 (4), pp.412-436. ⟨10.1038/s41588-022-01024-z⟩. ⟨hal-03668928⟩