Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[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 Bahrami  1 , Espen Hagen  1 , Julian Fuhrer  1 , Vera Fominykh  1 , Alexey Shadrin  1 , Tahir Tekin Filiz  1 , Lavinia Athanasiu  1 , Benjamin Grenier-Boley  3 , Céline Bellenguez  3 , Itziar de Rojas  4   5   6 , Fahri Küçükali  7   8 , Anja Schneider  9   10 , Luca Kleineidam  9   10 , Dan Rujescu  11   12 , Norbert Scherbaum  13 , Jürgen Deckert  14   15 , Steffi Riedel-Heller  16 , Lucrezia Hausner  17 , Laura Molina-Porcel  18   19   20 , Timo Grimmer  21 , Stefanie Heilmann-Heimbach  22 , Susanne Moebus  23 , Nikolaos Scarmeas  24   25 , Jose María García-Alberca  20   26 , Emilio Franco-Macías  27 , Pablo Mir  20   28   29 , Luis M Real  30   31   32 , Eloy Rodriguez-Rodriguez  20   33   34 , Jose Luís Royo  35 , María Eugenia Sáez  36 , Ángel Carracedo  37   38 , Adolfo Lopez de Munain  39   40 , Guillermo Amer-Ferrer  41 , Miguel Calero  20   42   43 , Miguel Medina  20 , Guillermo Garcia-Ribas  44 , 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 Soininen  55 , Sami Heikkinen  56 , Alexandre de Mendonça  57 , Shima Mehrabian  58 , Latchezar Traykov  58 , Jakub Hort  59 , Martin Vyhnalek  59   60 , Nicolai Sandau  61 , Jesper Qvist Thomassen  61 , Jiao Luo  61 , Yolande A L Pijnenburg  62 , Niccolo Tesi  62   63 , John van Swieten  64 , Vilmantas Giedraitis  65 , Julie Williams  66   67 , Gael Nicolas  68 , Stephanie Debette  69   70   71 , Philippe Amouyel  3 , Edna Grünblatt  72   73   74 , Julius Popp  75   76   77 , Paola Bossù  78 , Daniela Galimberti  79   80 , Giacomina Rossi  81 , Beatrice Arosio  82   83 , Patrizia Mecocci  84   85 , Alessio Squassina  86 , Lucio Tremolizzo  87   88 , Barbara Borroni  89   90 , Benedetta Nacmias  91   92 , Davide Seripa  93 , Innocenzo Rainero  94 , Antonio Daniele  95   96 , Fabrizio Piras  97 , Carlo Masullo  98 , Patrick Gavin Kehoe  99 , Ruth Frikke-Schmidt  61   100 , Roberta Ghidoni  90 , 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 Hiltunen  56 , Rebecca Sims  67 , Alfredo Ramirez  9   10   106   107   108 , Iris J Broce  109   110 , Jan Haavik  111   112 , Geir Selbæk  113   114   115 , Anne-Brita Knapskog  114 , Ingvild Saltvedt  116 , Sverre Bergh  115   117 , Eivind Aakhus  115 , Bjørn-Eivind Kirsebom  118 , Leiv Otto Watne  119 , Arvid Rongve  120   121 , Dag Årsland  122   123 , Srdjan Djurovic  1   124 , Eystein Stordal  125 , Mathias Toft  126   127 , Katja Scheffler  128   129 , Tormod Fladby  130   127 , Jean-Charles Lambert  3 , Anders Dale  109   131   132 , Oleksandr Frei  1   2 , Ole Andreassen  1
Affiliations

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

Bayram Cevdet Akdeniz et al. medRxiv. .

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 OR80/20 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 (OR80/20 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.

PubMed Disclaimer

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
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.
See this image and copyright information in PMC

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

Publication types

LinkOut - more resources