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New insights on the genetic etiology of Alzheimer’s and related dementia
Céline Bellenguez, Fahri Küçükali, Iris E. Jansen, Víctor Andrade, Sonia Moreno–Grau, Najaf Amin, Adam C. Naj, Benjamin Grenier‐Boley, Rafael Campos-Martín, Peter Holmans, Anne Boland, Luca Kleineidam, Vincent Damotte, Sven J. van der Lee, Teemu Kuulasmaa, Qiong Yang, Itziar de Rojas, Joshua C. Bis, Amber Yaqub, Ivana Nedeljković, Marcos R. Costa, Julien Chapuis, Shahzad Ahmad, Vilmantas Giedraitis, Merçé Boada, Dag Aarsland, Pablo García‐González, Carla Abdelnour, Emilio Alarcón‐Martín, Montserrat Alegret, Ignacio Álvarez, Victoria Álvarez, Nicola J. Armstrong, Anthoula Tsolaki, Carmen Antúnez, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Beatrice Arosio, Lavinia Athanasiu, Henri Bailly, Nerisa Banaj, Miquel Baquero, Ana Belén Pastor, Luisa Benussi, Claudine Berr, Céline Besse, Valentina Bessi, Giuliano Binetti, Alessandra Bizzarro, Daniel Alcolea, Rafael Blesa, Barbara Borroni, Silvia Boschi, Paola Bossù, Geir Bråthen, Catherine Bresner, Keeley J. Brookes, Luis Ignacio Brusco, Katharina Bürger, María J. Bullido, William S. Bush, Miguel Calero, Carole Dufouil, Ãngel Carracedo, Roberta Cecchetti, Laura Cervera‐Carles, Camille Charbonnier, Caterina Chillotti, Henry Brodaty, Simona Ciccone, Jurgen A.H.R. Claassen, Christopher Clark, Elisa Conti, Anaïs Corma‐Gómez, Emanuele Maria Costantini, Carlo Custodero, Delphine Daian, Carolina Dalmasso, Antonio Daniele, Efthimios Dardiotis, Jean‐François Dartigues, Peter Paul De Deyn, Kátia de Paiva Lopes, Lot D. de Witte, Stéphanie Debette, Jürgen Deckert, Teodoro del Ser, Nicola Denning, Anita L. DeStefano, Martin Dichgans, Janine Diehl‐Schmid, Mónica Díez-Fairén, Paolo Rossi, Srdjan Djurovic, Emmanuelle Duron, Emrah Düzel, Sebastiaan Engelborghs, Valentina Escott‐Price, Ana Espinosa, Dolores Buiza‐Rueda, Michael Ewers, Fabrizio Tagliavini, Lucia Farotti, Chiara Fenoglio, Marta Fernández‐Fuertes, John Hardy, Raffaele Ferrari, Catarina B. Ferreira, Evelyn Ferri, Bertrand Fin, Peter Fischer, Tormod Fladby, Klaus Fließbach, Juan Fortea, Silvia Fostinelli, Nick C. Fox, Emlio Franco-Macías, Ana Frank, Lutz Froelich, Daniela Galimberti, José María García‐Alberca, Sebastián García‐Madrona, Guillermo García‐Ribas, Geneviève Chêne, Roberta Ghidoni, Ina Giegling, Giorgio Giaccone, Oliver Goldhardt, Antonio González-Pérez, Caroline Graff, Giulia Grande, Emma Green, Timo Grimmer, Edna Grünblatt, Tamar Guetta‐Baranes, Annakaisa Haapasalo, Georgios M. Hadjigeorgiou, Jonathan L. Haines, Kara L. Hamilton‐Nelson, Harald Hampel, Olivier Hanon, Annette M. Hartmann, Lucrezia Hausner, Janet Harwood, Stefanie Heilmann‐Heimbach, Seppo Helisalmi, Michael T. Heneka, Isabel Hernández, Martin J. Herrmann, Per Hoffmann, Clive Holmes, Henne Holstege, Raquel Huerto Vilas, Marc Hulsman, Jack Humphrey, Geert Jan Biessels, Charlotte Johansson, Patrick G. Kehoe, Lena Kilander, Anne Kinhult Ståhlbom, Miia Kivipelto, Anne M. Koivisto, Johannes Kornhuber, Mary H. Kosmidis, Pavel P. Kuksa, Brian W. Kunkle, Carmen Lage, Erika J. Laukka, Alessandra Lauria, Chien‐Yueh Lee, Jenni Lehtisalo, Claudia L. Satizábal, Ondřej Lerch, Alberto Lleó, Rogelio León López, Oscar L. López, Seth Love, Malin Löwemark, Lauren Luckcuck, Juan Macı́as, Catherine Macleod, Wolfgang Maier, Francesca Mangialasche, Marco Spallazzi, Marta Marquié, Iain Marshall, Eden R. Martin, Ángel Martín Montes, Carmen Martínez Rodríguez, Carlo Masullo, Richard Mayeux, Simon Mead, Patrizia Mecocci, Miguel Medina, Alun Meggy, Silvia Mendoza, Manuel Menéndez‐González, Pablo Mir, María Teresa Periñán, Merel O. Mol, Laura Molina‐Porcel, Laura Montrreal, Laura Morelli, Fermín Moreno, Kevin Morgan, Markus M. Nöthen, Carolina Muchnik, Benedetta Nacmias, Tiia Ngandu, Gaël Nicolas, Børge G. Nordestgaard, Robert Olaso, Adelina Orellana, Michela Orsini, Gemma Ortega, Alessandro Padovani, Paolo Caffarra, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Pau Pástor, Alba Pérez‐Cordón, Jordi Pérez‐Tur, Pierre Péricard, Oliver Peters, Yolande A.L. Pijnenburg, Juan A. Pineda, Gerard Piñol‐Ripoll, Claudia Pisanu, Thomas Polak, Julius Popp, Daniëlle Posthuma, Josef Priller, Raquel Puerta, Olivier Quenez, Inés Quintela, Jesper Qvist Thomassen, Alberto Rábano, Innocenzo Rainero, Inez H.G.B. Ramakers, Luís Miguel Real, Marcel Reinders, Steffi G. Riedel‐Heller, Peter Riederer, Eloy Rodríguez‐Rodríguez, Arvid Rongve, Irene Rosas Allende, Maitée Rosende-Roca, José Luís Royo, Elisa Rubino, Dan Rujescu, María Eugenia Sáez, Paraskevi Sakka, Ingvild Saltvedt, Ángela Sanabria, María Bernal Sánchez‐Arjona, Florentino Sánchez-García, Shima Mehrabian, Pascual Sánchez‐Juan, Raquel Sánchez‐Valle, Sigrid Botne Sando, Michela Scamosci, Nikolaos Scarmeas, Elio Scarpini, Philip Scheltens, Norbert Scherbaum, Martin Scherer, Matthias Schmid, Anja Schneider, Jonathan M. Schott, Geir Selbæk, Jin Sha, Alexey Shadrin, Olivia Anna Skrobot, Gijsje J. L. Snijders, Hilkka Soininen, Vincenzo Solfrizzi, Alina Solomon, Sandro Sorbi, Óscar Sotolongo‐Grau, Gianfranco Spalletta, Annika Spottke, Alessio Squassina, Juan Pablo Tartari, Lluís Tárraga, Niccoló Tesi, Anbupalam Thalamuthu, Thomas Tegos, Latchezar Traykov, Lucio Tremolizzo, Anne Tybjærg‐Hansen, André G. Uitterlinden, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Christine Van Broeckhoven, Aad van der Lugt, Jasper Van Dongen, Jeroen van Rooij, John C. van Swieten, Rik Vandenberghe, Frans Verhey, Jean‐Sébastien Vidal, Jonathan Vogelgsang, Martin Vyhnálek, Michael Wagner, David Wallon, Li‐San Wang, Ruiqi Wang, Leonie Weinhold, Jens Wiltfang, Gill Windle, Bob Woods, Mary Yannakoulia, Yi Zhao, Miren Zulaica, Manuel Serrano‐Ríos, Davide Seripa, Eystein Stordal, Lindsay A. Farrer, Bruce M. Psaty, Mohsen Ghanbari, Towfique Raj, Perminder S. Sachdev, Karen A. Mather, Frank Jessen, M. Arfan Ikram, Alexandre de Mendonça, Jakub Hort, Magda Tsolaki, Margaret A. Pericak‐Vance, Philippe Amouyel, Julie Williams, Ruth Frikke‐Schmidt, Jordi Clarimón, Jean‐François 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, Agustı́n Ruiz, Alfredo Ramı́rez, Jean‐Charles Lambert
Bibliographic record
VenuemedRxiv · 2020
Typepreprint
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsnot available
FundersNational Institute of Biomedical Imaging and BioengineeringNational Institute of Neurological Disorders and StrokeNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Mental HealthNational Institute on AgingCenter for Innovative MedicineInstituto de Salud Carlos IIINational Institutes of HealthAssociazione Italiana Ricerca AlzheimerUK Dementia Research InstituteMedical Research CouncilAcademy of FinlandGrifolsServierMinisterio de Economía y CompetitividadUniversity College London Hospitals NHS Foundation TrustIXICODemensfondenSahlgrenska UniversitetssjukhusetNovo NordiskVetenskapsrådetSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungStockholms Läns LandstingBanco Bilbao Vizcaya ArgentariaCanadian Institutes of Health ResearchEuropean CommissionKnut och Alice Wallenbergs StiftelseFundación Salud 2000Université de LilleKarolinska InstitutetJuho Vainion SäätiöMinisterstvo Zdravotnictví Ceské RepublikyFonds Wetenschappelijk OnderzoekNational Health and Medical Research CouncilSuomen KulttuurirahastoUniverzita Karlova v PrazeGeneralitat de CatalunyaBundesministerium für Bildung und ForschungAXA Research FundMinistero della SaluteH. Lundbeck A/SInstitut National de la Santé et de la Recherche MédicaleUniversität HeidelbergVlaamse regeringNational Institute for Health and Care ResearchCardiff UniversityNational Research FoundationUniversity of NottinghamGenentechFondation pour la Recherche sur AlzheimerSocialdepartementetBioClinicaNewcastle UniversityUniversitat de BarcelonaKing's College LondonUniversity of CambridgeNovartis Pharmaceuticals CorporationMotor Neurone Disease AssociationNational Institute for Social Care and Health ResearchUniversiteit AntwerpenMinisterstvo Školství, Mládeže a TělovýchovyHigher Education Funding Council for WalesDipartimenti di EccellenzaUniversity of California, San DiegoAlzheimer's SocietyCentro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasDevelopment of Innovative Strategies for a Transdisciplinary approach to ALZheimer's diseaseSorbonne UniversitéNorthern California Institute for Research and EducationSouth London and Maudsley NHS Foundation TrustLudwig Boltzmann GesellschaftEuropean Regional Development FundAlzheimer's Research TrustU.S. Department of DefenseHersenstichtingBrightFocus FoundationEli Lilly and CompanyNorth Bristol NHS TrustItä-Suomen YliopistoFundação para a Ciência e a TecnologiaEU Joint Programme – Neurodegenerative Disease ResearchPfizerWellcome TrustAgence Nationale de la RechercheBiogenEisaiUniversity of Southern CaliforniaFoundation for the National Institutes of HealthMinistero dell’Istruzione, dell’Università e della RicercaFundación BBVAF. Hoffmann-La RocheSeinäjoen KeskussairaalaVanderbilt UniversityMeso Scale DiagnosticsYrjö Jahnssonin SäätiöU.S. Department of Veterans AffairsConsortium canadien en neurodégénérescence associée au vieillissementBristol-Myers SquibbSigrid Juséliuksen SäätiöStichting MS ResearchUniversity of SouthamptonEconomic and Social Research CouncilOffice of Research and DevelopmentStichting ALS NederlandAlzheimer's Association
KeywordsDementiaDiseaseAlzheimer's diseaseFrontotemporal dementiaGenome-wide association studyNeuroscienceBioinformaticsBiologyMedicineGeneGeneticsInternal medicineSingle-nucleotide polymorphismGenotype
Abstract
ABSTRACT Alzheimer’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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.002
metaresearch head score (Gemma)0.003
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.003
Threshold uncertainty score0.012
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.032
GPT teacher head0.268
Teacher spread0.236 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations90
Published2020
Admission routes1
Has abstractyes