Machine learning in Alzheimer’s disease genetics

Bracher-Smith M, Melograna F, Ulm B, Bellenguez C, Grenier-Boley B, Duroux D, Nevado AJ, Holmans P, Tijms BM, Hulsman M, de Rojas I, Campos-Martin R, der Lee Sv, Castillo A, Küçükali F, Peters O, Schneider A, Dichgans M, Rujescu D, Scherbaum N, Deckert J, Riedel-Heller S, Hausner L, Molina-Porcel L, Düzel E, Grimmer T, Wiltfang J, Heilmann-Heimbach S, Moebus S, Tegos T, Scarmeas N, Dols-Icardo O, Moreno F, Pérez-Tur J, Bullido MJ, Pastor P, Sánchez-Valle R, Álvarez V, Boada M, Puerta R, Mir P, Real LM, Piñol-Ripoll G, Rodriguez-Rodriguez E, Soininen H, Heikkinen S, de Mendonça A, Mehrabian S, Traykov L, Hort J, Vyhnalek M, Sandau N, Thomassen JQ, Pijnenburg YA, Holstege H, van Swieten J, Ramakers I, Verhey F, Scheltens P, Graff C, Papenberg G, Giedraitis V, Williams J, Amouyel P, Boland A, Deleuze JF, Nicolas G, Dufouil C, Pasquier F, Hanon O, Debette S, Grünblatt E, Popp J, Ghidoni R, Galimberti D, Arosio B, Mecocci P, Solfrizzi V, Parnetti L, Squassina A, Tremolizzo L, Borroni B, Nacmias B, Spallazzi M, Seripa D, Rainero I, Daniele A, Piras F, Masullo C, Rossi G, Jessen F, Kehoe P, Magda T, Sánchez-Juan P, Sleegers K, Ingelsson M, Hiltunen M, Sims R, van der Flier W, Andreassen OA, Ruiz A, Ramirez A, Ikram MA, Mather K, Sachdev P, Ghanbari M, Zulaica M, Yannakoulia M, Woods B, Windle G, Weinhold L, Wallon D, Wagner M, Vogelgsang J, Vita MG, Vidal JS, Vandenberghe R, van Rooij J, Van Dongen J, Van Broeckhoven C, Valero S, Ulstein I, Ullgren A, Uitterlinden A, Tybjærg-Hansen A, Thomas T, Thalamuthu A, Tesí N, Tárraga L, Miguel A, Stordal E, Spottke A, Sotolongo-Grau O, Sorbi S, Solomon A, Skrobot O, Shadrin AA, Selbæk G, Schott JM, Schmid M, Scherer M, Scarpini E, Scamosci M, Sando SB, Sanchez-Garcia F, Sánchez-Arjona MB, García-Gutierrez F, Saltvedt I, Sakka P, Sáez ME, Rubino E, Royo JL, Rosende-Roca M, Allende IR, Rongve A, Olivé C, Riederer P, Reinders MJ, Rábano A, Quintela I, Quenez O, Puerta R, Priller J, Posthuma D, Polak T, Pisanu C, Pineda JA, Pericard P, Martinez-Lucas M, Paolo C, Padovani A, Capdevila M, Orsini M, Orellana A, Olaso R, Nordestgaard BG, Ngandu T, Nöthen MM, Morgan K, Montrreal L, Mol M, Menéndez-González M, Mendoza S, Meggy A, Medina M, Mead S, Rodríguez CM, Montes AM, Marshall R, Marquié M, Marco S, Mangialasche F, Maier W, MacLeod CA, Macías J, Luckcuck L, Löwemark M, Love S, de Munain AL, Lleó A, Lerch O, Lehtisalo J, Lauria A, Laukka EJ, Lage C, Kosmidis MH, Kornhuber J, Koivisto A, Kivipelto M, Ståhlbom AK, Kilander L, Johansson C, Jan Biessels G, Vilas RH, Holmes C, Hoffmann P, Herrmann MJ, Hernández I, Heneka MT, Helisalmi S, Harwood J, Leonenko G, Hartmann AM, Hardy J, Hampel H, Hadjigeorgiou G, Haapasalo A, Guetta-Baranes T, Green E, Grande G, González-Pérez A, Goldhardt O, Giorgio G, Giegling I, Garcia-Ribas G, Garcia-Madrona S, García-González P, García-Alberca JM, Froelich L, Frank-García A, Franco-Macías E, Fox NC, Fostinelli S, Foroud TM, Fortea J, Fließbach K, Fladby T, Fischer P, Fin B, Ferri E, Ferreira CB, Fernández-Fuertes M, Fenoglio C, Farotti L, Nielsen SF, Fabrizio T, Ewers M, Blázquez J, Engelborghs S, Duron E, Djurovic S, Rossi PD, Diez-Fairen M, Diehl-Schmid J, Denning N, del Ser T, de Deyn PP, Dartigues JF, Dardiotis E, Daian D, Custodero C, Giuffrè GM, Corma-Gómez A, Conti E, Clark C, Clarimon J, Claassen JA, Ciccone S, Chillotti C, Charbonnier C, Cervera-Carles L, Cecchetti R, Carracedo Á, Chene G, Calero M, Burholt V, Bûrger K, Buiza-Rueda D, Brookes KJ, Brodaty H, Bresner C, Bråthen G, Bossù P, Boschi S, Boada M, Blesa R, Bizarro A, Bellini S, Binetti G, Bessi V, Besse C, Berr C, Pastor AB, Baquero M, Banaj N, Bailly H, Athanasiu L, Pastor AA, Archetti S, Arcaro M, Appollonio I, Anthoula T, Armstrong NJ, Alvarez I, Alegret M, Alcolea D, Alarcón-Martín E, Abdelnour C, Cano A, Aarsland D, Ahmad S, Kleineidam L, Dalmasso MC, Fernández V, Andrade V, van der Lee S, Jansen I, Frikke-Schmidt R, Amin N, Roshchupkin G, Lambert JC, Van Steen K, van Duijn C, Escott-Price V (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 16

Article Number: 6726

Journal Issue: 1

DOI: 10.1038/s41467-025-61650-z

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.

Authors with CRIS profile

Involved external institutions

Klinikum der Universität München (LMU Klinikum) Germany (DE) University of Eastern Finland Finland (FI) Biomedical Research Networking Center on Neurodegenerative Diseases / Centro de Investigación Biomédica en Red Enfermedades neurodegenerativas (CIBERNED) Spain (ES) Cardiff University United Kingdom (GB) Vrije Universiteit Brussel (VUB) Belgium (BE) Université Paris-Sud France (FR) University of Oslo Norway (NO) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT) MútuaTerrassa University Hospital / Hospital Universitario MútuaTerrassa / Hospital Universitari MútuaTerrassa Spain (ES) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Rigshospitalet Denmark (DK) University of Oxford United Kingdom (GB) Motol University Hospital / Fakultní nemocnice v Motole Czech Republic (CZ) Universitätsklinikum Würzburg Germany (DE) Fondazione Policlinico Universitario Agostino Gemelli IRCCS Italy (IT) Università degli Studi di Cagliari Italy (IT) Karolinska Institute Sweden (SE) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Hospital Universitario Virgen de Valme Spain (ES) Universitätsklinikum Köln Germany (DE) Aristotle University of Thessaloniki Greece (GR) Université de Lille (ULille) / University of Lille Nord de France / Université Lille Nord de France / Université Lille II France (FR) Erasmus University Medical Center (MC) Netherlands (NL) Fondazione Santa Lucia IRCCS Italy (IT) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) University of Nottingham United Kingdom (GB) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona Spain (ES) Cambridge Institute of Public Health United Kingdom (GB) Universitat Internacional de Catalunya Spain (ES) Centro Andaluz de Estudios Bioinformáticos (CAEBi) Spain (ES) Technische Universität München (TUM) Germany (DE) Stavanger University Hospital Norway (NO) Foundation of the Carlo Besta Neurological Institute (IRCCS) Italy (IT) Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Germany (DE) Centro de Investigación de Enfermedades Neurológicas (CIEN) Spain (ES) Medizinische Universität Wien Austria (AT) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) University College London (UCL) United Kingdom (GB) Université de Bordeaux France (FR) European University Cyprus (EUC) / Ευρωπαϊκό Πανεπιστήμιο Κύπρου Cyprus (CY) University of Thessaly / Πανεπιστήμιο Θεσσαλίας Greece (GR) Hospital Universitario Ramón y Cajal Spain (ES) University of Auckland New Zealand (NZ) Hospitales Universitarios Virgen Macarena y Virgen del Rocío Spain (ES) Nottingham Trent University United Kingdom (GB) University of New South Wales (UNSW) Australia (AU) IRCCS Fatebenefratelli - Brescia Italy (IT) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) Sozialmedizinisches Zentrum Ost – Donauspital (SMZ Ost) Austria (AT) Università degli Studi di Firenze / University of Florence Italy (IT) University of Lisbon / Universidade de Lisboa (ULisboa) Portugal (PT) National Center of Human Genomics Research / Centre National de Recherche en Génomique Humaine (CNRGH) France (FR) Neuropsychiatrie : recherche épidémiologique et clinique France (FR) Hospital Universitario y Politécnico de La Fe Spain (ES) Uppsala University Sweden (SE) Università degli Studi di Brescia Italy (IT) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Harokopio University / Χαροκόπειο Πανεπιστήμιο Greece (GR) Bangor University United Kingdom (GB) Hospital Universitario de Gran Canaria Doctor Negrín Spain (ES) University of Santiago de Compostela / Universidad de Santiago de Compostela (USC) Spain (ES) Università degli studi di Milano Italy (IT) Università degli Studi di Perugia Italy (IT) Gentofte Hospital Denmark (DK) Hospital Universitari de Santa Maria Spain (ES) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia Italy (IT) University of Milano-Bicocca / Università degli Studi di Milano-Bicocca, UNIMIB Italy (IT) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Université de Lille (ULille, UDL) France (FR) Medical University Sofia / Медицински университет Bulgaria (BG) University of Liège (ULg) / Université de Liège Belgium (BE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Universität Duisburg-Essen (UDE) Germany (DE) Universität Leipzig Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Klinikum rechts der Isar Germany (DE) Universitätsklinikum Göttingen Germany (DE) Universitätsklinikum Bonn Germany (DE) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universitätsklinikum Essen Germany (DE) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) The Athens Association of Alzheimer Disease and Related Disorders (AAADRD) Greece (GR) Gertrude H. Sergievsky Center United States (USA) (US) University of Rouen / Université de Rouen France (FR) Bordeaux Population Health (BPH) France (FR) Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino Italy (IT) Universidad de Málaga / University of Malaga Spain (ES) Fundació per la Docència i Recerca MútuaTerrassa Spain (ES) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Central University Hospital of Asturias Spain (ES) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Haugesund sjukehus Norway (NO) ISPA Instituto de Investigación Sanitaria del Principado de Asturias Spain (ES) University of Bari Aldo Moro / Università degli Studi di Bari Aldo Moro Italy (IT) The Andalusian Institute for Neuroscience (IANEC) / Instituto Andaluz de Neurociencia Spain (ES) Azienda Ospedaliero-Universitaria di Parma / Parma University Hospital Italy (IT) Ospedale Vito Fazzi Italy (IT) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Delft University of Technology (TU Delft) Netherlands (NL) University of Parma / Università degli Studi di Parma Italy (IT) University of Bristol United Kingdom (GB) University of Southampton United Kingdom (GB) Indiana University United States (USA) (US) VIB-KU Leuven Center for Brain & Disease Research Belgium (BE) University of Copenhagen Denmark (DK) National Institute for Health and Welfare (THL) Finland (FI) Institute Born-Bunge Belgium (BE) Azienda Ospedaliera Universitaria di Cagliari Italy (IT) Namsos Hospital Norway (NO) Maastricht University Netherlands (NL) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL)

How to cite

APA:

Bracher-Smith, M., Melograna, F., Ulm, B., Bellenguez, C., Grenier-Boley, B., Duroux, D.,... Escott-Price, V. (2025). Machine learning in Alzheimer’s disease genetics. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-61650-z

MLA:

Bracher-Smith, Matthew, et al. "Machine learning in Alzheimer’s disease genetics." Nature Communications 16.1 (2025).

BibTeX: Download