Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation

doi:10.1101/2025.07.28.25332293

This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2025 Jul 28:2025.07.28.25332293.

doi: 10.1101/2025.07.28.25332293.

Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation

Bayram Cevdet Akdeniz^{1

2}, Shahram Bahrami¹, Espen Hagen¹, Julian Fuhrer¹, Vera Fominykh¹, Alexey Shadrin¹, Tahir Tekin Filiz¹, Lavinia Athanasiu¹, Benjamin Grenier-Boley³, Céline Bellenguez³, Itziar de Rojas^{4

5

6}, Fahri Küçükali^{7

8}, Anja Schneider^{9

10}, Luca Kleineidam^{9

10}, Dan Rujescu^{11

12}, Norbert Scherbaum¹³, Jürgen Deckert^{14

15}, Steffi Riedel-Heller¹⁶, Lucrezia Hausner¹⁷, Laura Molina-Porcel^{18

19

20}, Timo Grimmer²¹, Stefanie Heilmann-Heimbach²², Susanne Moebus²³, Nikolaos Scarmeas^{24

25}, Jose María García-Alberca^{20

26}, Emilio Franco-Macías²⁷, Pablo Mir^{20

28

29}, Luis M Real^{30

31

32}, Eloy Rodriguez-Rodriguez^{20

33

34}, Jose Luís Royo³⁵, María Eugenia Sáez³⁶, Ángel Carracedo^{37

38}, Adolfo Lopez de Munain^{39

40}, Guillermo Amer-Ferrer⁴¹, Miguel Calero^{20

42

43}, Miguel Medina²⁰, Guillermo Garcia-Ribas⁴⁴, Maite Mendioroz^{45

46}, Oriol Dols-Icardo^{20

47}, Fermin Moreno^{20

39

48}, Jordi Pérez-Tur^{20

49}, María J Bullido^{20

50

51

52}, Victoria Álvarez^{53

54}, Hilkka Soininen⁵⁵, Sami Heikkinen⁵⁶, Alexandre de Mendonça⁵⁷, Shima Mehrabian⁵⁸, Latchezar Traykov⁵⁸, Jakub Hort⁵⁹, Martin Vyhnalek^{59

60}, Nicolai Sandau⁶¹, Jesper Qvist Thomassen⁶¹, Jiao Luo⁶¹, Yolande A L Pijnenburg⁶², Niccolo Tesi^{62

63}, John van Swieten⁶⁴, Vilmantas Giedraitis⁶⁵, Julie Williams^{66

67}, Gael Nicolas⁶⁸, Stephanie Debette^{69

70

71}, Philippe Amouyel³, Edna Grünblatt^{72

73

74}, Julius Popp^{75

76

77}, Paola Bossù⁷⁸, Daniela Galimberti^{79

80}, Giacomina Rossi⁸¹, Beatrice Arosio^{82

83}, Patrizia Mecocci^{84

85}, Alessio Squassina⁸⁶, Lucio Tremolizzo^{87

88}, Barbara Borroni^{89

90}, Benedetta Nacmias^{91

92}, Davide Seripa⁹³, Innocenzo Rainero⁹⁴, Antonio Daniele^{95

96}, Fabrizio Piras⁹⁷, Carlo Masullo⁹⁸, Patrick Gavin Kehoe⁹⁹, Ruth Frikke-Schmidt^{61

100}, Roberta Ghidoni⁹⁰, Agustín Ruiz^{4

5

101

102}, Victoria Fernandez^{4

5}, Pascual Sánchez-Juan^{5

103}, Kristel Sleegers^{7

8}, Martin Ingelsson^{65

104

105}, Mikko Hiltunen⁵⁶, Rebecca Sims⁶⁷, Alfredo Ramirez^{9

10

106

107

108}, Iris J Broce^{109

110}, Jan Haavik^{111

112}, Geir Selbæk^{113

114

115}, Anne-Brita Knapskog¹¹⁴, Ingvild Saltvedt¹¹⁶, Sverre Bergh^{115

117}, Eivind Aakhus¹¹⁵, Bjørn-Eivind Kirsebom¹¹⁸, Leiv Otto Watne¹¹⁹, Arvid Rongve^{120

121}, Dag Årsland^{122

123}, Srdjan Djurovic^{1

124}, Eystein Stordal¹²⁵, Mathias Toft^{126

127}, Katja Scheffler^{128

129}, Tormod Fladby^{130

127}, Jean-Charles Lambert³, Anders Dale^{109

131

132}, Oleksandr Frei^{1

2}, Ole Andreassen¹

Affiliations

¹ Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
² Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosicences, University of Oslo, Oslo, Norway.
³ Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, LabEx DISTALZ - U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
⁴ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
⁵ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
⁶ Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
⁷ Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁸ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁰ Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
¹¹ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
¹² Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
¹³ Department of Psychiatry and Psychotherapy, LVR-University Hospital Essen, Medical Faculty of the University of Duisburg-Essen, Essen, Germany.
¹⁴ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Germany.
¹⁵ Institute of Clinical Epidemiology and Biometrics, Julius-Maximilians-University Würzburg, Würzburg, Germany.
¹⁶ Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, 04103 Leipzig, Germany.
¹⁷ Department of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Germany.
¹⁸ Neurological Tissue Bank - Biobanc- Hospital Clinic -IDIBAPS, Barcelona, Spain.
¹⁹ Alzheimer's disease and other cognitive disorders Unit, Neurology Department, Hospital Clinic, Barcelona, Spain.
²⁰ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
²¹ Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, TUM University Hospital, Technical University of Munich, School of Medicine, Munich, Germany.
²² Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
²³ Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany.
²⁴ Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, NY, USA.
²⁵ 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
²⁶ Alzheimer Research Center & Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain.
²⁷ Unidad de Demencias, Servicio de Neurología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
²⁸ Unidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
²⁹ Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain.
³⁰ Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain.
³¹ Departamento de Bioquímica Médica, Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
³² CIBERINFEC, Network Center for Biomedical Research in Infectious Diseases, National Institute of Health Carlos III, Madrid, Spain.
³³ Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain.
³⁴ Departamento de Medicina y Psiquiatría, Universidad de Cantabria, Santander, Spain.
³⁵ Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
³⁶ CAEBI, Centro Andaluz de Estudios Bioinformáticos, Sevilla, Spain.
³⁷ Grupo de Medicina Xenómica, Centro en Red de Investigación en Enfermedades Raras (CIBERER-ISCIII), CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
³⁸ Fundación de Medicina Xenómica, Servicio Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.
³⁹ Department of Neurology, Hospital Universitario Donostia-Instituto Biodonostia-OSAKIDETZA-EHU-CIBERNED, San Sebastian, Spain.
⁴⁰ Department of Neurosciences, Faculty of Medicine and Nursery, University of the Basque Country, San Sebastián, Spain.
⁴¹ Department of Neurology, Hospital Universitario Son Espases, Palma, Spain.
⁴² Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Madrid, Spain.
⁴³ CIEN Foundation/Queen Sofia Foundation Alzheimer Center, Madrid, Spain.
⁴⁴ Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.
⁴⁵ Navarrabiomed, Pamplona, Spain.
⁴⁶ Department of Neurology, Hospital Universitario de Navarra, Pamplona, Spain.
⁴⁷ Sant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁴⁸ Biogipuzkoa Health Research Institute, Neurosciences Area, Group of Neurodegenerative Diseases, 20014 San Sebastián, Spain.
⁴⁹ Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain.
⁵⁰ Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain.
⁵¹ Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain.
⁵² Universidad Autónoma de Madrid, Madrid, Spain.
⁵³ Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain.
⁵⁴ Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
⁵⁵ Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
⁵⁶ Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
⁵⁷ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁵⁸ Clinic of Neurology, UH "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria.
⁵⁹ Memory Clinic, Department of Neurology, Charles University, Second Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
⁶⁰ International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
⁶¹ Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁶² Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
⁶³ Delft Bioinformatics Lab, Delft University of technology, Delft, The Netherlands.
⁶⁴ Department of Neurology, ErasmusMC, Rotterdam, The Netherlands.
⁶⁵ Dept. of Public Health and Caring Sciences / Geriatrics, Uppsala University, Uppsala, Sweden.
⁶⁶ UKDRI@ Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
⁶⁷ Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
⁶⁸ Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Genetics and CNR-MAJ, F-76000 Rouen, France.
⁶⁹ University of Bordeaux, Inserm Bordeaux Population Health Research Center U1219, Bordeaux, France.
⁷⁰ CHU de Bordeaux, Pole santé publique, Bordeaux, France.
⁷¹ Institut du Cerveau (ICM), Paris Brain Institute, INSERM U1127, UMR CNRS 7225 Paris, Sorbonne Université, Assistance Publique des Hôpitaux de Paris, Paris, France.
⁷² Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.
⁷³ Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
⁷⁴ Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
⁷⁵ Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
⁷⁶ Department of Adult Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland.
⁷⁷ Institute for Regenerative Medicine, University of Zürich, Zürich, Switzerland.
⁷⁸ Experimental Neuro-psychobiology Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy.
⁷⁹ Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.
⁸⁰ Dept. of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
⁸¹ Unit of Neurology 8, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁸² Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
⁸³ Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
⁸⁴ Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
⁸⁵ Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
⁸⁶ Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
⁸⁷ Neurology Unit, IRCCS "San Gerardo dei Tintori", Monza, Italy.
⁸⁸ School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
⁸⁹ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹⁰ Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
⁹¹ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
⁹² IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁹³ Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy.
⁹⁴ Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.
⁹⁵ Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
⁹⁶ Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
⁹⁷ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
⁹⁸ Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.
⁹⁹ Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁰⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁰¹ Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁰² Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health San Antonio, TX 78229-3900, USA.
¹⁰³ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, Spain.
¹⁰⁴ Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
¹⁰⁵ Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹⁰⁶ Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰⁷ Department of Psychiatry & Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
¹⁰⁸ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany.
¹⁰⁹ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
¹¹⁰ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
¹¹¹ Department of Biomedicine, University of Bergen, Bergen, Norway.
¹¹² Bergen Center for Brain Plasticity, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
¹¹³ Faculty of Medicine, University of Oslo, Oslo, Norway.
¹¹⁴ Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
¹¹⁵ Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹¹⁶ Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway and Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹¹⁷ Research Centre for Age-related Functional Decline and Disease, Innlandet Hospital Trust, Ottestad, Norway.
¹¹⁸ Department of Neurology, University Hospital of North Norway, Tromsø; Department of Psychology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
¹¹⁹ Oslo Delirium Research Group, Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway.
¹²⁰ Department of Research and Innovation, Helse Fonna, Haugesund, Norway.
¹²¹ University of Bergen, Department of Clinical Medicine (K1), Bergen, Norway.
¹²² Centre for Age - Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹²³ Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹²⁴ Department of Medical Genetics, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹²⁵ Department of Psychiatry, Namsos Hospital, Namsos, Norway.
¹²⁶ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹²⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹²⁸ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.
¹²⁹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
¹³⁰ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹³¹ Department of Radiology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
¹³² Department of Cognitive Science, University of California San Diego, La Jolla, CA, USA.

PMID: 40766162
PMCID: PMC12324663
DOI: 10.1101/2025.07.28.25332293

Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation

Bayram Cevdet Akdeniz et al. medRxiv. 2025.

[Preprint]. 2025 Jul 28:2025.07.28.25332293.

doi: 10.1101/2025.07.28.25332293.

Authors

Affiliations

¹ Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
² Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosicences, University of Oslo, Oslo, Norway.
³ Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, LabEx DISTALZ - U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
⁴ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
⁵ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
⁶ Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
⁷ Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁸ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁰ Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
¹¹ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
¹² Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
¹³ Department of Psychiatry and Psychotherapy, LVR-University Hospital Essen, Medical Faculty of the University of Duisburg-Essen, Essen, Germany.
¹⁴ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Germany.
¹⁵ Institute of Clinical Epidemiology and Biometrics, Julius-Maximilians-University Würzburg, Würzburg, Germany.
¹⁶ Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, 04103 Leipzig, Germany.
¹⁷ Department of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Germany.
¹⁸ Neurological Tissue Bank - Biobanc- Hospital Clinic -IDIBAPS, Barcelona, Spain.
¹⁹ Alzheimer's disease and other cognitive disorders Unit, Neurology Department, Hospital Clinic, Barcelona, Spain.
²⁰ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
²¹ Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, TUM University Hospital, Technical University of Munich, School of Medicine, Munich, Germany.
²² Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
²³ Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany.
²⁴ Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, NY, USA.
²⁵ 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
²⁶ Alzheimer Research Center & Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain.
²⁷ Unidad de Demencias, Servicio de Neurología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
²⁸ Unidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
²⁹ Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain.
³⁰ Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain.
³¹ Departamento de Bioquímica Médica, Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
³² CIBERINFEC, Network Center for Biomedical Research in Infectious Diseases, National Institute of Health Carlos III, Madrid, Spain.
³³ Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain.
³⁴ Departamento de Medicina y Psiquiatría, Universidad de Cantabria, Santander, Spain.
³⁵ Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
³⁶ CAEBI, Centro Andaluz de Estudios Bioinformáticos, Sevilla, Spain.
³⁷ Grupo de Medicina Xenómica, Centro en Red de Investigación en Enfermedades Raras (CIBERER-ISCIII), CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
³⁸ Fundación de Medicina Xenómica, Servicio Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.
³⁹ Department of Neurology, Hospital Universitario Donostia-Instituto Biodonostia-OSAKIDETZA-EHU-CIBERNED, San Sebastian, Spain.
⁴⁰ Department of Neurosciences, Faculty of Medicine and Nursery, University of the Basque Country, San Sebastián, Spain.
⁴¹ Department of Neurology, Hospital Universitario Son Espases, Palma, Spain.
⁴² Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Madrid, Spain.
⁴³ CIEN Foundation/Queen Sofia Foundation Alzheimer Center, Madrid, Spain.
⁴⁴ Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.
⁴⁵ Navarrabiomed, Pamplona, Spain.
⁴⁶ Department of Neurology, Hospital Universitario de Navarra, Pamplona, Spain.
⁴⁷ Sant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁴⁸ Biogipuzkoa Health Research Institute, Neurosciences Area, Group of Neurodegenerative Diseases, 20014 San Sebastián, Spain.
⁴⁹ Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain.
⁵⁰ Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain.
⁵¹ Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain.
⁵² Universidad Autónoma de Madrid, Madrid, Spain.
⁵³ Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain.
⁵⁴ Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
⁵⁵ Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
⁵⁶ Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
⁵⁷ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁵⁸ Clinic of Neurology, UH "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria.
⁵⁹ Memory Clinic, Department of Neurology, Charles University, Second Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
⁶⁰ International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
⁶¹ Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁶² Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
⁶³ Delft Bioinformatics Lab, Delft University of technology, Delft, The Netherlands.
⁶⁴ Department of Neurology, ErasmusMC, Rotterdam, The Netherlands.
⁶⁵ Dept. of Public Health and Caring Sciences / Geriatrics, Uppsala University, Uppsala, Sweden.
⁶⁶ UKDRI@ Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
⁶⁷ Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
⁶⁸ Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Genetics and CNR-MAJ, F-76000 Rouen, France.
⁶⁹ University of Bordeaux, Inserm Bordeaux Population Health Research Center U1219, Bordeaux, France.
⁷⁰ CHU de Bordeaux, Pole santé publique, Bordeaux, France.
⁷¹ Institut du Cerveau (ICM), Paris Brain Institute, INSERM U1127, UMR CNRS 7225 Paris, Sorbonne Université, Assistance Publique des Hôpitaux de Paris, Paris, France.
⁷² Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.
⁷³ Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
⁷⁴ Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
⁷⁵ Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
⁷⁶ Department of Adult Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland.
⁷⁷ Institute for Regenerative Medicine, University of Zürich, Zürich, Switzerland.
⁷⁸ Experimental Neuro-psychobiology Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy.
⁷⁹ Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.
⁸⁰ Dept. of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
⁸¹ Unit of Neurology 8, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁸² Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
⁸³ Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
⁸⁴ Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
⁸⁵ Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
⁸⁶ Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
⁸⁷ Neurology Unit, IRCCS "San Gerardo dei Tintori", Monza, Italy.
⁸⁸ School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
⁸⁹ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁹⁰ Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
⁹¹ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
⁹² IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁹³ Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy.
⁹⁴ Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.
⁹⁵ Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
⁹⁶ Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
⁹⁷ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
⁹⁸ Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.
⁹⁹ Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁰⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁰¹ Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁰² Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health San Antonio, TX 78229-3900, USA.
¹⁰³ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, Spain.
¹⁰⁴ Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
¹⁰⁵ Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹⁰⁶ Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰⁷ Department of Psychiatry & Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
¹⁰⁸ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany.
¹⁰⁹ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
¹¹⁰ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
¹¹¹ Department of Biomedicine, University of Bergen, Bergen, Norway.
¹¹² Bergen Center for Brain Plasticity, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
¹¹³ Faculty of Medicine, University of Oslo, Oslo, Norway.
¹¹⁴ Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
¹¹⁵ Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹¹⁶ Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway and Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹¹⁷ Research Centre for Age-related Functional Decline and Disease, Innlandet Hospital Trust, Ottestad, Norway.
¹¹⁸ Department of Neurology, University Hospital of North Norway, Tromsø; Department of Psychology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
¹¹⁹ Oslo Delirium Research Group, Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway.
¹²⁰ Department of Research and Innovation, Helse Fonna, Haugesund, Norway.
¹²¹ University of Bergen, Department of Clinical Medicine (K1), Bergen, Norway.
¹²² Centre for Age - Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹²³ Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹²⁴ Department of Medical Genetics, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹²⁵ Department of Psychiatry, Namsos Hospital, Namsos, Norway.
¹²⁶ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹²⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹²⁸ Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.
¹²⁹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
¹³⁰ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹³¹ Department of Radiology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
¹³² Department of Cognitive Science, University of California San Diego, La Jolla, CA, USA.

PMID: 40766162
PMCID: PMC12324663
DOI: 10.1101/2025.07.28.25332293

Abstract

Objectives: Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer's disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models.

Methods: We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E (APOE) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model.

Results: The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR_80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 - 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR_80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset.

Conclusion: Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

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Conflict of interest statement

Conflict of interests: Dr. Anders M. Dale is Founding Director, holds equity in CorTechs Labs, Inc. (DBA Cortechs.ai), and serves on its Board of Directors and Scientific Advisory Board. Dr. Dale is the President of J. Craig Venter Institute (JCVI) and is a member of the Board of Trustees of JCVI. He is an unpaid consultant for Oslo University Hospital. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. Dr. Andreassen has received speaker fees from Lundbeck, Janssen, Otsuka, Lilly, and Sunovion and is a consultant to Cortechs.ai. and Precision Health. Dr. Frei is a consultant to Precision Health. GS has participated in Advisory Board meetings for Roche, Eli-Lilly and Eisai regarding disease-modifying drugs for Alzheimer’s disease. GS has received honoraria for delivering lectures at symposia sponsored by Eisai and Eli-Lilly. Dan Rujescu served as consultant for Boehringer-Ingelheim and Janssen, received honoraria from Boehringer-Ingelheim, Gerot Lannacher, Indorsia, Janssen and Pharmagenetix, received research/travel support from Angelini, Boehringer-Ingelheim, Janssen and Schwabe, and served on advisory boards of AC Immune, Boehringer-Ingelheim, Indorsia, Roche and Rovi. Timo Grimmer reported receiving consulting fees from Acumen, Advantage Ther, Alector, Anavex, Biogen, BMS; Cogthera, Eisai, Eli Lilly, Functional Neuromod.,Grifols, Janssen, Neurimmune, Noselab, Novo Nordisk, Roche Diagnostics, and Roche Pharma; lecture fees from Anavex, Cogthera, Eisai, Eli Lilly, FEO, Grifols, Pfizer, Roche Pharma, Schwabe, and Synlab; and has received grants to his institution from Biogen, Eisai and Eli Lilly.

Figures

**Figure 1**
Kaplan-Meier (KM) curves and Cox proportional hazard model fits from the whole European Alzheimer & Dementia Biobank (EADB) dataset used to develop EADB Polygenic Hazard Score (PHS) model. a) Stratification of all EADB samples with respect to EADB720, b) Stratification of only *APOE* neutral (ε3/3) samples with respect to EADB720. The proportional hazard assumptions were checked based on graphical comparisons between KM estimates with 95% confidence intervals and Cox proportional hazard models (See Table 2 for numerical comparison). The vertical green-dashed line at 0.5 is to show the ages when risk groups reach 0.5 probability of Alzheimer’s disease (AD)-free survival.

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References

1. Liu C.-C., Liu C.-C., Kanekiyo T., Xu H., and Bu G., ‘Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.’, Nat Rev Neurol, vol. 9, no. 2, pp. 106–118, Feb. 2013, doi: 10.1038/nrneurol.2012.263. - DOI - PMC - PubMed
1. ‘2012 Alzheimer’s disease facts and figures.’, Alzheimers Dement, vol. 8, no. 2, pp. 131–168, 2012, doi: 10.1016/j.jalz.2012.02.001. - DOI - PubMed
1. Ertekin-Taner N., ‘Genetics of Alzheimer’s disease: a centennial review.’, Neurol Clin, vol. 25, no. 3, pp. 611–667, v, Aug. 2007, doi: 10.1016/j.ncl.2007.03.009. - DOI - PMC - PubMed
1. Jackson R. J., Hyman B. T., and Serrano-Pozo A., ‘Multifaceted roles of APOE in Alzheimer disease.’, Nat Rev Neurol, vol. 20, no. 8, pp. 457–474, Aug. 2024, doi: 10.1038/s41582-024-00988-2. - DOI - PMC - PubMed
1. Baker E. et al. , ‘What does heritability of Alzheimer’s disease represent?’, PLoS One, vol. 18, no. 4, p. e0281440, 2023, doi: 10.1371/journal.pone.0281440. - DOI - PMC - PubMed

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[1] Liu C.-C., Liu C.-C., Kanekiyo T., Xu H., and Bu G., ‘Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.’, Nat Rev Neurol, vol. 9, no. 2, pp. 106–118, Feb. 2013, doi: 10.1038/nrneurol.2012.263. - DOI - PMC - PubMed

[2] Liu C.-C., Liu C.-C., Kanekiyo T., Xu H., and Bu G., ‘Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.’, Nat Rev Neurol, vol. 9, no. 2, pp. 106–118, Feb. 2013, doi: 10.1038/nrneurol.2012.263. - DOI - PMC - PubMed

[3] ‘2012 Alzheimer’s disease facts and figures.’, Alzheimers Dement, vol. 8, no. 2, pp. 131–168, 2012, doi: 10.1016/j.jalz.2012.02.001. - DOI - PubMed

[4] ‘2012 Alzheimer’s disease facts and figures.’, Alzheimers Dement, vol. 8, no. 2, pp. 131–168, 2012, doi: 10.1016/j.jalz.2012.02.001. - DOI - PubMed

[5] Ertekin-Taner N., ‘Genetics of Alzheimer’s disease: a centennial review.’, Neurol Clin, vol. 25, no. 3, pp. 611–667, v, Aug. 2007, doi: 10.1016/j.ncl.2007.03.009. - DOI - PMC - PubMed

[6] Ertekin-Taner N., ‘Genetics of Alzheimer’s disease: a centennial review.’, Neurol Clin, vol. 25, no. 3, pp. 611–667, v, Aug. 2007, doi: 10.1016/j.ncl.2007.03.009. - DOI - PMC - PubMed

[7] Jackson R. J., Hyman B. T., and Serrano-Pozo A., ‘Multifaceted roles of APOE in Alzheimer disease.’, Nat Rev Neurol, vol. 20, no. 8, pp. 457–474, Aug. 2024, doi: 10.1038/s41582-024-00988-2. - DOI - PMC - PubMed

[8] Jackson R. J., Hyman B. T., and Serrano-Pozo A., ‘Multifaceted roles of APOE in Alzheimer disease.’, Nat Rev Neurol, vol. 20, no. 8, pp. 457–474, Aug. 2024, doi: 10.1038/s41582-024-00988-2. - DOI - PMC - PubMed

[9] Baker E. et al. , ‘What does heritability of Alzheimer’s disease represent?’, PLoS One, vol. 18, no. 4, p. e0281440, 2023, doi: 10.1371/journal.pone.0281440. - DOI - PMC - PubMed

[10] Baker E. et al. , ‘What does heritability of Alzheimer’s disease represent?’, PLoS One, vol. 18, no. 4, p. e0281440, 2023, doi: 10.1371/journal.pone.0281440. - DOI - PMC - PubMed

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Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation

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Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation

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