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Machine learning in Alzheimer's disease genetics.
Bracher-Smith, M. ; Melograna, F. ; Ulm, B. ; Bellenguez, C. ; Grenier-Boley, B. ; Duroux, D. ; Nevado, A. J. ; Holmans, P. ; Tijms, B. M. ; Hulsman, M. ; de Rojas, I. ; Campos-Martin, R. ; der Lee, S. v. ; Castillo, A. ; Küçükali, F. ; Peters, O.DZNE* ; Schneider, A.DZNE* ; Dichgans, M.DZNE* ; Rujescu, D. ; Scherbaum, N. ; Deckert, J. ; Riedel-Heller, S. ; Hausner, L. ; Molina-Porcel, L. ; Düzel, E.DZNE* ; Grimmer, T. ; Wiltfang, J.DZNE* ; Heilmann-Heimbach, S. ; Moebus, S. ; Tegos, T. ; Scarmeas, N. ; Dols-Icardo, O. ; Moreno, F. ; Pérez-Tur, J. ; Bullido, M. J. ; Pastor, P. ; Sánchez-Valle, R. ; Álvarez, V. ; Boada, M. ; García-González, P. ; Puerta, R. ; Mir, P. ; Real, L. M. ; Piñol-Ripoll, G. ; García-Alberca, J. M. ; Rodriguez-Rodriguez, E. ; Soininen, H. ; Heikkinen, S. ; de Mendonça, A. ; Mehrabian, S. ; Traykov, L. ; Hort, J. ; Vyhnalek, M. ; Sandau, N. ; Thomassen, J. Q. ; Pijnenburg, Y. A. L. ; Holstege, H. ; van Swieten, J. ; Ramakers, I. ; Verhey, F. ; Scheltens, P. ; Graff, C. ; Papenberg, G. ; Giedraitis, V. ; Williams, J. ; Amouyel, P. ; Boland, A. ; Deleuze, J.-F. ; 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. ; Wagner, M.DZNE* ; Nacmias, B. ; Spallazzi, M. ; Seripa, D. ; Rainero, I. ; Daniele, A. ; Piras, F. ; Masullo, C. ; Rossi, G. ; Jessen, F.DZNE* ; Kehoe, P. ; Magda, T. ; Sánchez-Juan, P. ; Sleegers, K. ; Ingelsson, M. ; Hiltunen, M. ; Sims, R. ; van der Flier, W. ; Andreassen, O. A. ; Ruiz, A. ; Ramirez, A.DZNE* ; EADB (Collaboration Author) ; Frikke-Schmidt, R. ; Amin, N. ; Roshchupkin, G. ; Lambert, J.-C. ; Van Steen, K. ; van Duijn, C. ; Escott-Price, V. ; Jansen, I. (Contributor) ; van der Lee, S. (Contributor) ; Andrade, V. (Contributor) ; Fernández, V. (Contributor) ; Dalmasso, M.-C. (Contributor) ; Kleineidam, L. (Contributor)Extern* ; Ahmad, S. (Contributor) ; Aarsland, D. (Contributor) ; Cano, A. (Contributor) ; Abdelnour, C. (Contributor) ; Alarcón-Martín, E. (Contributor) ; Alcolea, D. (Contributor) ; Alegret, M. (Contributor) ; Alvarez, I. (Contributor) ; Armstrong, N. J. (Contributor) ; Anthoula, T. (Contributor) ; Appollonio, I. (Contributor) ; Arcaro, M. (Contributor) ; Archetti, S. (Contributor) ; Pastor, A. A. (Contributor) ; Athanasiu, L. (Contributor) ; Bailly, H. (Contributor) ; Banaj, N. (Contributor) ; Baquero, M. (Contributor) ; Pastor, A. B. (Contributor) ; Berr, C. (Contributor) ; Besse, C. (Contributor) ; Bessi, V. (Contributor) ; Binetti, G. (Contributor) ; Fostinelli, S. (Contributor) ; Bellini, S. (Contributor) ; Bizarro, A. (Contributor) ; Blesa, R. (Contributor) ; Boada, M. (Contributor) ; Boschi, S. (Contributor) ; Bossù, P. (Contributor) ; Bråthen, G. (Contributor) ; Bresner, C. (Contributor) ; Brodaty, H. (Contributor) ; Brookes, K. J. (Contributor) ; Buiza-Rueda, D. (Contributor) ; Bürger, K. (Contributor)Extern* ; Burholt, V. (Contributor) ; Calero, M. (Contributor) ; Chene, G. (Contributor) ; Carracedo, Á. (Contributor) ; Cecchetti, R. (Contributor) ; Cervera-Carles, L. (Contributor) ; Charbonnier, C. (Contributor) ; Chillotti, C. (Contributor) ; Ciccone, S. (Contributor) ; Claassen, J. A. H. R. (Contributor) ; Clarimon, J. (Contributor) ; Clark, C. (Contributor) ; Conti, E. (Contributor) ; Corma-Gómez, A. (Contributor) ; Giuffrè, G. M. (Contributor) ; Custodero, C. (Contributor) ; Daian, D. (Contributor) ; Dardiotis, E. (Contributor) ; Dartigues, J.-F. (Contributor) ; de Deyn, P. P. (Contributor) ; Del Ser, T. (Contributor) ; Denning, N. (Contributor) ; Diehl-Schmid, J. (Contributor) ; Diez-Fairen, M. (Contributor) ; Rossi, P. D. (Contributor) ; Djurovic, S. (Contributor) ; Duron, E. (Contributor) ; Engelborghs, S. (Contributor) ; Blázquez, J. (Contributor) ; Ewers, M. (Contributor) ; Fabrizio, T. (Contributor) ; Nielsen, S. F. (Contributor) ; Farotti, L. (Contributor) ; Fenoglio, C. (Contributor) ; Fernández-Fuertes, M. (Contributor) ; Ferreira, C. B. (Contributor) ; Ferri, E. (Contributor) ; Fin, B. (Contributor) ; Fischer, P. (Contributor) ; Fladby, T. (Contributor) ; Fließbach, K. (Contributor)Extern* ; Fortea, J. (Contributor) ; Foroud, T. M. (Contributor) ; Fostinelli, S. (Contributor) ; Fox, N. C. (Contributor) ; Franco-Macías, E. (Contributor) ; Frank-García, A. (Contributor) ; Froelich, L. (Contributor) ; García-Alberca, J. M. (Contributor) ; García-González, P. (Contributor) ; Garcia-Madrona, S. (Contributor) ; Garcia-Ribas, G. (Contributor) ; Giegling, I. (Contributor) ; Giorgio, G. (Contributor) ; Goldhardt, O. (Contributor) ; González-Pérez, A. (Contributor) ; Grande, G. (Contributor) ; Green, E. (Contributor) ; Guetta-Baranes, T. (Contributor) ; Haapasalo, A. (Contributor) ; Hadjigeorgiou, G. (Contributor) ; Hampel, H. (Contributor) ; Hardy, J. (Contributor) ; Hartmann, A. M. (Contributor) ; Leonenko, G. (Contributor) ; Harwood, J. (Contributor) ; Helisalmi, S. (Contributor) ; Heneka, M. T. (Contributor) ; Hernández, I. (Contributor) ; Herrmann, M. J. (Contributor) ; Hoffmann, P. (Contributor) ; Holmes, C. (Contributor) ; Vilas, R. H. (Contributor) ; Hulsman, M. (Contributor) ; Jan Biessels, G. (Contributor) ; Johansson, C. (Contributor) ; Kilander, L. (Contributor) ; Ståhlbom, A. K. (Contributor) ; Kivipelto, M. (Contributor) ; Koivisto, A. (Contributor) ; Kornhuber, J. (Contributor) ; Kosmidis, M. H. (Contributor) ; Lage, C. (Contributor) ; Laukka, E. J. (Contributor) ; Lauria, A. (Contributor) ; Lehtisalo, J. (Contributor) ; Lerch, O. (Contributor) ; Lleó, A. (Contributor) ; de Munain, A. L. (Contributor) ; Love, S. (Contributor) ; Löwemark, M. (Contributor) ; Luckcuck, L. (Contributor) ; Macías, J. (Contributor) ; MacLeod, C. A. (Contributor) ; Maier, W. (Contributor) ; Mangialasche, F. (Contributor) ; Marco, S. (Contributor) ; Marquié, M. (Contributor) ; Marshall, R. (Contributor) ; Montes, A. M. (Contributor) ; Rodríguez, C. M. (Contributor) ; Mead, S. (Contributor) ; Medina, M. (Contributor) ; Meggy, A. (Contributor) ; Mendoza, S. (Contributor) ; Menéndez-González, M. (Contributor) ; Mol, M. (Contributor) ; Montrreal, L. (Contributor) ; Morgan, K. (Contributor) ; Nöthen, M. M. (Contributor) ; Ngandu, T. (Contributor) ; Nordestgaard, B. G. (Contributor) ; Olaso, R. (Contributor) ; Orellana, A. (Contributor) ; Orsini, M. (Contributor) ; Capdevila, M. (Contributor) ; Padovani, A. (Contributor) ; Paolo, C. (Contributor) ; Martinez-Lucas, M. (Contributor) ; Pericard, P. (Contributor) ; Pineda, J. A. (Contributor) ; Pisanu, C. (Contributor) ; Polak, T. (Contributor) ; Posthuma, D. (Contributor) ; Priller, J. (Contributor)Extern* ; Puerta, R. (Contributor) ; Quenez, O. (Contributor) ; Quintela, I. (Contributor) ; Rábano, A. (Contributor) ; Reinders, M. J. T. (Contributor) ; Riederer, P. (Contributor) ; Olivé, C. (Contributor) ; Rongve, A. (Contributor) ; Allende, I. R. (Contributor) ; Rosende-Roca, M. (Contributor) ; Royo, J. L. (Contributor) ; Rubino, E. (Contributor) ; Sáez, M. E. (Contributor) ; Sakka, P. (Contributor) ; Saltvedt, I. (Contributor) ; García-Gutierrez, F. (Contributor) ; Sánchez-Arjona, M. B. (Contributor) ; Sanchez-Garcia, F. (Contributor) ; Sánchez-Juan, P. (Contributor) ; Sánchez-Valle, R. (Contributor) ; Sando, S. B. (Contributor) ; Scamosci, M. (Contributor) ; Scarpini, E. (Contributor) ; Scherer, M. (Contributor) ; Schmid, M. (Contributor)Extern* ; Schott, J. M. (Contributor) ; Selbæk, G. (Contributor) ; Shadrin, A. A. (Contributor) ; Skrobot, O. (Contributor) ; Solomon, A. (Contributor) ; Sorbi, S. (Contributor) ; Sotolongo-Grau, O. (Contributor) ; Spottke, A. (Contributor)Extern* ; Stordal, E. (Contributor) ; Miguel, A. (Contributor) ; Tárraga, L. (Contributor) ; Tesí, N. (Contributor) ; Thalamuthu, A. (Contributor) ; Thomas, T. (Contributor) ; Traykov, L. (Contributor) ; Tybjærg-Hansen, A. (Contributor) ; Uitterlinden, A. (Contributor) ; Ullgren, A. (Contributor) ; Ulstein, I. (Contributor) ; Valero, S. (Contributor) ; Van Broeckhoven, C. (Contributor) ; Van Dongen, J. (Contributor) ; van Rooij, J. (Contributor) ; Vandenberghe, R. (Contributor) ; Vidal, J.-S. (Contributor) ; Vita, M. G. (Contributor) ; Vogelgsang, J. (Contributor) ; Wagner, M. (Contributor)Extern* ; Wallon, D. (Contributor) ; Weinhold, L. (Contributor) ; Windle, G. (Contributor) ; Woods, B. (Contributor) ; Yannakoulia, M. (Contributor) ; Zulaica, M. (Contributor) ; Ghanbari, M. (Contributor) ; Sachdev, P. (Contributor) ; Mather, K. (Contributor) ; Ikram, M. A. (Contributor)
2025
Springer Nature
[London]
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Please use a persistent id in citations: 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.
Keyword(s): Alzheimer Disease: genetics (MeSH) ; Humans (MeSH) ; Machine Learning (MeSH) ; Genome-Wide Association Study (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Algorithms (MeSH) ; GTPase-Activating Proteins: genetics (MeSH) ; Neural Networks, Computer (MeSH) ; GTPase-Activating Proteins
Contributing Institute(s):
- Biomarker-Assisted Early Detection of Dementias (AG Peters)
- Translational Dementia Research (Bonn) (AG Schneider)
- Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
- Clinical Neurophysiology and Memory (AG Düzel)
- Molecular biomarkers for predictive diagnostics of neurodegenerative diseases (AG Wiltfang)
- Neuropsychology (AG Wagner)
- Clinical Alzheimer’s Disease Research (AG Jessen)
- Patient Studies (Bonn) (Patient Studies (Bonn))
Research Program(s):
- 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
Appears in the scientific report
2025
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