Machine learning in Alzheimer’s disease genetics

Matthew Bracher-Smith, Federico Melograna, Brittany Ulm, Céline Bellenguez, Benjamin Grenier-Boley, Diane Duroux, Alejo J. Nevado, Peter Holmans, Betty M. Tijms, Marc Hulsman, Itziar Rojas, Rafael Campos-Martin, Sven van Lee, Atahualpa Castillo, Fahri Küçükali, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J. Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M. Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Sami Heikkinen, Alexandre Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnalek, Nicolai Sandau, Jesper Qvist Thomassen, Yolande A. L. Pijnenburg, Henne Holstege, John Swieten, Inez Ramakers, Frans Verhey, Philip Scheltens, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Julie Williams, Philippe Amouyel, Anne Boland, Jean-François Deleuze, Gael Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Michael Wagner, Benedetta Nacmias, Marco Spallazzi, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Fabrizio Piras, Carlo Masullo, Giacomina Rossi, Frank Jessen, Patrick Kehoe, Tsolaki Magda, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Mikko Hiltunen, Rebecca Sims, Wiesje Flier, Ole A. Andreassen, Agustín Ruiz, Alfredo Ramirez, Ruth Frikke-Schmidt, Najaf Amin, Gennady Roshchupkin, Jean-Charles Lambert, Kristel Steen (), Cornelia Duijn () and Valentina Escott-Price ()
Additional contact information
Matthew Bracher-Smith: Cardiff University
Federico Melograna: KU Leuven
Brittany Ulm: University of Oxford
Céline Bellenguez: LabEx DISTALZ - U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement
Benjamin Grenier-Boley: LabEx DISTALZ - U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement
Diane Duroux: University of Liege
Alejo J. Nevado: University of Oxford
Peter Holmans: Cardiff University
Betty M. Tijms: Amsterdam UMC
Marc Hulsman: Amsterdam UMC
Itziar Rojas: ACE Alzheimer Center Barcelona. Universitat Internacional de Catalunya
Rafael Campos-Martin: University of Cologne
Sven van Lee: Amsterdam UMC
Atahualpa Castillo: Cardiff University
Fahri Küçükali: VIB
Oliver Peters: German Center for Neurodegenerative Diseases (DZNE)
Anja Schneider: German Center for Neurodegenerative Diseases (DZNE)
Martin Dichgans: LMU Munich
Dan Rujescu: Medical University of Vienna
Norbert Scherbaum: Germany Medical Faculty
Jürgen Deckert: University Hospital of Würzburg
Steffi Riedel-Heller: University of Leipzig
Lucrezia Hausner: University of Heidelberg
Laura Molina-Porcel: and University of Barcelona
Emrah Düzel: German Center for Neurodegenerative Diseases (DZNE)
Timo Grimmer: Klinikum rechts der Isar
Jens Wiltfang: University Medical Center Goettingen
Stefanie Heilmann-Heimbach: School of Medicine & University Hospital Bonn
Susanne Moebus: University Hospital of University Duisburg-Essen
Thomas Tegos: Aristotle University of Thessaloniki
Nikolaos Scarmeas: Columbia University
Oriol Dols-Icardo: Universitat Autònoma de Barcelona
Fermin Moreno: National Institute of Health Carlos III
Jordi Pérez-Tur: National Institute of Health Carlos III
María J. Bullido: National Institute of Health Carlos III
Pau Pastor: Terrassa
Raquel Sánchez-Valle: University of Barcelona
Victoria Álvarez: Laboratorio de Genética. Hospital Universitario Central de Asturias
Mercè Boada: National Institute of Health Carlos III
Pablo García-González: Universitat Internacional de Catalunya
Raquel Puerta: Universitat Internacional de Catalunya
Pablo Mir: National Institute of Health Carlos III
Luis M. Real: Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme
Gerard Piñol-Ripoll: Hospital Universitari Santa Maria de Lleida
Jose María García-Alberca: National Institute of Health Carlos III
Eloy Rodriguez-Rodriguez: National Institute of Health Carlos III
Hilkka Soininen: University of Eastern Finland
Sami Heikkinen: University of Eastern Finland
Alexandre Mendonça: University of Lisbon
Shima Mehrabian: Medical University - Sofia
Latchezar Traykov: Medical University - Sofia
Jakub Hort: Second Faculty of Medicine and Motol University Hospital
Martin Vyhnalek: 2nd Faculty of Medicine and Motol University Hospital
Nicolai Sandau: Copenhagen University Hospital - Rigshospitalet
Jesper Qvist Thomassen: Copenhagen University Hospital - Rigshospitalet
Yolande A. L. Pijnenburg: Amsterdam UMC
Henne Holstege: Amsterdam UMC
John Swieten: ErasmusMC
Inez Ramakers: Alzheimer Center Limburg
Frans Verhey: Alzheimer Center Limburg
Philip Scheltens: Amsterdam UMC
Caroline Graff: Karolinska University Hospital-Solna
Goran Papenberg: Karolinska Institutet and Stockholm University
Vilmantas Giedraitis: Uppsala University
Julie Williams: Cardiff University
Philippe Amouyel: LabEx DISTALZ - U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement
Anne Boland: Centre National de Recherche en Génomique Humaine
Jean-François Deleuze: Centre National de Recherche en Génomique Humaine
Gael Nicolas: F-
Carole Dufouil: Univ Bordeaux
Florence Pasquier: CHU Clinical and Research Memory Research Centre (CMRR) of Distalz Lille France
Olivier Hanon: Hôpital Broca
Stéphanie Debette: Bordeaux Population Health Research Center
Edna Grünblatt: University of Zurich
Julius Popp: Department of Psychiatry
Roberta Ghidoni: IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli
Daniela Galimberti: Ospedale Policlinico
Beatrice Arosio: University of Milan
Patrizia Mecocci: University of Perugia
Vincenzo Solfrizzi: University of Bari “A. Moro”
Lucilla Parnetti: University of Perugia
Alessio Squassina: University of Cagliari
Lucio Tremolizzo: Monza and University of Milano-Bicocca
Barbara Borroni: IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli
Michael Wagner: German Center for Neurodegenerative Diseases (DZNE)
Benedetta Nacmias: Drug Research and Child Health University of Florence
Marco Spallazzi: University-Hospital of Parma
Davide Seripa: Vito Fazzi Hospital
Innocenzo Rainero: University of Torino
Antonio Daniele: Università Cattolica del Sacro Cuore
Fabrizio Piras: IRCCS Santa Lucia Foundation
Carlo Masullo: Catholic University of the Sacred Heart
Giacomina Rossi: Fondazione IRCCS Istituto Neurologico Carlo Besta
Frank Jessen: German Center for Neurodegenerative Diseases (DZNE)
Patrick Kehoe: University of Bristol
Tsolaki Magda: Aristotle University of Thessaloniki
Pascual Sánchez-Juan: National Institute of Health Carlos III
Kristel Sleegers: VIB
Martin Ingelsson: Uppsala University
Mikko Hiltunen: University of Eastern Finland
Rebecca Sims: Cardiff University
Wiesje Flier: Amsterdam UMC
Ole A. Andreassen: Oslo University Hospital
Agustín Ruiz: National Institute of Health Carlos III
Alfredo Ramirez: University of Cologne
Ruth Frikke-Schmidt: Copenhagen University Hospital - Rigshospitalet
Najaf Amin: University of Oxford
Gennady Roshchupkin: Erasmus MC
Jean-Charles Lambert: LabEx DISTALZ - U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement
Kristel Steen: KU Leuven
Cornelia Duijn: University of Oxford
Valentina Escott-Price: Cardiff University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer’s disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61650-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61650-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61650-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().