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Bellenguez, Celine; Kucukali, Fahri; Jansen, Iris E.; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C.; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A.; Boland, Anne; Damotte, Vincent; Lee, Sven J. van der; Costa, Marcos R.; Kuulasmaa, Teemu; Yang, Qiong; De Rojas, Itziar; Bis, Joshua C.; Yaqub, Amber; Prokic, Ivana; Chapuis, Julien; Ahmad, Shahzad; Giedraitis, Vilmantas; Aarsland, Dag; Garcia-Gonzalez, Pablo; Abdelnour, Carla; Alarcon-Martin, Emilio; Alcolea, Daniel; Alegret, Montserrat; Alvarez, Ignacio; Alvarez, Victoria; Armstrong, Nicola J.; Tsolaki, Anthoula; Antunez, Carmen; Appollonio, Ildebrando; Arcaro, Marina; Archetti, Silvana; Arias Pastor, Alfonso; Arosio, Beatrice; Athanasiu, Lavinia; Bailly, Henri; Banaj, Nerisa; Baquero, Miquel; Barral, Sandra; Beiser, Alexa; Pastor, Ana Belen; Below, Jennifer E.; Benchek, Penelope; Benussi, Luisa; Berr, Claudine; Besse, Celine; Bessi, Valentina; Binetti, Giuliano; Bizarro, Alessandra; Blesa, Rafael; Boada, Merce; Boerwinkle, Eric; Borroni, Barbara; Boschi, Silvia; Bossu, Paola; Brathen, Geir; Bressler, Jan; Bresner, Catherine; Brodaty, Henry; Brookes, Keeley J.; Ignacio Brusco, Luis; Buiza-Rueda, Dolores; Burger, Katharina; Burholt, Vanessa; Bush, William S.; Calero, Miguel; Cantwell, Laura B.; Chene, Genevieve; Chung, Jaeyoon; Cuccaro, Michael L.; Cecchetti, Roberta; Cervera-Carles, Laura; Charbonnier, Camille; Chen, Hung-Hsin; Chillotti, Caterina; Ciccone, Simona; Claassen, Jürgen A. H. R.; Clark, Christopher; Conti, Elisa; Corma-Gomez, Anais; Costantini, Emanuele; Custodero, Carlo; Daian, Delphine; Dalmasso, Maria Carolina; Daniele, Antonio; Dardiotis, Efthimios; Dartigues, Jean-Francois; de Deyn, Peter Paul; Lopes, Katia de Paiva; De Witte, Lot D.; Debette, Stephanie; Deckert, Jürgen; del Ser, Teodoro; Denning, Nicola; Destefano, Anita; Dichgans, Martin; Diehl-Schmid, Janine; Diez-Fairen, Monica; Rossi, Paolo Dionigi; Djurovic, Srdjan; Duron, Emmanuelle; Duzel, Emrah; Dufouil, Carole; Eiriksdottir, Gudny; Engelborghs, Sebastiaan; Escott-Price, Valentina; Espinosa, Ana; Ewers, Michael; Faber, Kelley M.; Fabrizio, Tagliavini; Nielsen, Sune Fallgaard; Fardo, David W.; Farotti, Lucia; Fenoglio, Chiara; Fernandez-Fuertes, Marta; Ferrari, Raffaele; Ferreira, Catarina B.; Ferri, Evelyn; Fin, Bertrand; Fischer, Peter; Fladby, Tormod; Fliessbach, Klaus; Fongang, Bernard; Fornage, Myriam; Fortea, Juan; Foroud, Tatiana M.; Fostinelli, Silvia; Fox, Nick C.; Franco-Macias, Emlio; Bullido, Maria J.; Frank-Garcia, Ana; Froelich, Lutz; Fulton-Howard, Brian; Galimberti, Daniela; Maria Garcia-Alberca, Jose; Garcia-Madrona, Sebastian; Garcia-Ribas, Guillermo; Ghidoni, Roberta; Giegling, Ina; Giorgio, Giaccone; Goate, Alison M.; Goldhardt, Oliver; Gomez-Fonseca, Duber; Gonzalez-Perez, Antonio; Graff, Caroline; Grande, Giulia; Green, Emma; Grimmer, Timo; Grunblatt, Edna; Grunin, Michelle; Gudnason, Vilmundur; Guetta-Baranes, Tamar; Haapasalo, Annakaisa; Hadjigeorgiou, Georgios; Haines, Jonathan L.; Hamilton-Nelson, Kara L.; Hampel, Harald; Hanon, Olivier; Hardy, John; Hartmann, Annette M.; Hausner, Lucrezia; Harwood, Janet; Heilmann-Heimbach, Stefanie; Helisalmi, Seppo; Heneka, Michael T.; Hernandez, Isabel; Herrmann, Martin J.; Hoffmann, Per; Holmes, Clive; Holstege, Henne; Huerto Vilas, Raquel; Hulsman, Marc; Humphrey, Jack; Biessels, Geert Jan; Jian, Xueqiu; Johansson, Charlotte; Jun, Gyungah R.; Kastumata, Yuriko; Kauwe, John; Kehoe, Patrick G.; Kilander, Lena; Stahlbom, Anne Kinhult; Kivipelto, Miia; Koivisto, Anne; Kornhuber, Johannes; Kosmidis, Mary H.; Kukull, Walter A.; Kuksa, Pavel P.; Kunkle, Brian W.; Kuzma, Amanda B.; Lage, Carmen; Laukka, Erika J.; Launer, Lenore; Lauria, Alessandra; Lee, Chien-Yueh; Lehtisalo, Jenni; Lerch, Ondrej; Lleo, Alberto; Longstreth, William; Lopez, Oscar; Lopez de Munain, Adolfo; Love, Seth; Lowemark, Malin; Luckcuck, Lauren; Lunetta, Kathryn L.; Ma, Yiyi; Macias, Juan; Macleod, Catherine A.; Maier, Wolfgang; Mangialasche, Francesca; Spallazzi, Marco; Marquie, Marta; Marshall, Rachel; Martin, Eden R.; Martin Montes, Angel; Martinez Rodriguez, Carmen; Masullo, Carlo; Mayeux, Richard; Mead, Simon; Mecocci, Patrizia; Medina, Miguel; Meggy, Alun; Mehrabian, Shima; Mendoza, Silvia; Menendez-Gonzalez, Manuel; Mir, Pablo; Moebus, Susanne; Mol, Merel; Molina-Porcel, Laura; Montrreal, Laura; Morelli, Laura; Moreno, Fermin; Morgan, Kevin; Mosley, Thomas; Nothen, Markus M.; Muchnik, Carolina; Mukherjee, Shubhabrata; Nacmias, Benedetta; Ngandu, Tiia; Nicolas, Gael; Nordestgaard, Borge G.; Olaso, Robert; Orellana, Adelina; Orsini, Michela; Ortega, Gemma; Padovani, Alessandro; Paolo, Caffarra; Papenberg, Goran; Parnetti, Lucilla; Pasquier, Florence; Pastor, Pau; Peloso, Gina; Perez-Cordon, Alba; Perez-Tur, Jordi; Pericard, Pierre; Peters, Oliver; Pijnenburg, Yolande A. L.; Pineda, Juan A.; Pinol-Ripoll, Gerard; Pisanu, Laudia; Polak, Thomas; Popp, Julius; Posthuma, Danielle; Priller, Josef; Puerta, Raquel; Quenez, Olivier; Quintela, Ines; Thomassen, Jesper Qvist; Rabano, Alberto; Rainero, Innocenzo; Rajabli, Farid; Ramakers, Inez; Real, Luis M.; Reinders, Marcel J. T.; Reitz, Christiane; Reyes-Dumeyer, Dolly; Ridge, Perry; Riedel-Heller, Steffi; Riederer, Peter; Roberto, Natalia; Rodriguez-Rodriguez, Eloy; Rongve, Arvid; Rosas Allende, Irene; Rosende-Roca, Maitee; Luis Royo, Jose; Rubino, Elisa; Rujescu, Dan; Eugenia Saez, Maria; Sakka, Paraskevi; Saltvedt, Ingvild; Bernal Sanchez-Arjona, Maria; Sanchez-Garcia, Florentino; Sanchez Juan, Pascual; Sanchez-Valle, Raquel; Sando, Sigrid B.; Sarnowski, Chloe; Satizabal, Claudia L.; Scamosci, Michela; Scarmeas, Nikolaos; Scarpini, Elio; Scheltens, Philip; Scherbaum, Norbert; Scherer, Martin; Schmid, Matthias; Schneider, Anja; Schott, Jonathan M.; Selbaek, Geir; Seripa, Davide; Serrano, Manuel; Sha, Jin; Shadrin, Alexey A.; Skrobot, Olivia; Slifer, Susan; Snijders, Gijsje J. L.; Soininen, Hilkka; Solfrizzi, Vincenzo; Solomon, Alina; Song, Yeunjoo; Sorbi, Sandro; Sotolongo-Grau, Oscar; Spalletta, Gianfranco; Spottke, Annika; Squassina, Alessio; Stordal, Eystein; Pablo Tartan, Juan; Tarraga, Lluis; Tesi, Niccolo; Thalamuthu, Anbupalam; Thomas, Tegos; Tosto, Giuseppe; Traykov, Latchezar; Tremolizzo, Lucio; Tybjaerg-Hansen, Anne; Uitterlinden, Andre; Ullgren, Abbe; Ulstein, Ingun; Valero, Sergi; Valladares, Otto; Broeckhoven, Christine van; Vance, Jeffery; Vardarajan, Badri N.; Lugt, Aad van der; Dongen, Jasper van; Rooij, Jeroen van; Swieten, John van; Vandenberghe, Rik; Verhey, Frans; Vidal, Jean-Sebastien; Vogelgsang, Jonathan; Vyhnalek, Martin; Wagner, Michael; Wallon, David; Wang, Li-San; Wang, Ruiqi; Weinhold, Leonie; Wiltfang, Jens; Windle, Gill; Woods, Bob; Yannakoulia, Mary; Zare, Habil; Zhao, Yi; Zhang, Xiaoling; Zhu, Congcong; Zulaica, Miren; Farrer, Lindsay A.; Psaty, Bruce M.; Ghanbari, Mohsen; Raj, Towfique; Sachdev, Perminder; Mather, Karen; Jessen, Frank; Ikram, M. Arfan; de Mendonca, Alexandre; Hort, Jakub; Tsolaki, Magda; Pericak-Vance, Margaret A.; Amouyel, Philippe; Williams, Julie; Frikke-Schmidt, Ruth; Clarimon, Jordi; Deleuze, Jean-Francois; Rossi, Giacomina; Seshadri, Sudha; Andreassen, Ole A.; Ingelsson, Martin; Hiltunen, Mikko; Sleegers, Kristel; Schellenberg, Gerard D.; Duijn, Cornelia M. van; Sims, Rebecca; Flier, Wiesje M. van der; Ruiz, Agustin; Ramirez, Alfredo and Lambert, Jean-Charles (2022): New insights into the genetic etiology of Alzheimer's disease and related dementias. In: Nature Genetics, Vol. 54, No. 4: pp. 412-436

Full text not available from 'Open Access LMU'.

Abstract

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 epsilon 4 allele. Meta-analysis of genome-wide association studies on Alzheimer's disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer's disease and dementia.

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