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Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score
Open accessPublished version of a preprint
Abstract
BACKGROUND: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. METHODS AND FINDINGS: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. CONCLUSIONS: We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.
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“risk and seems to provide an improved method for risk prediction over more selective PRS or standard predictors such as APOEε4 alleles, age, and sex [118, 122, 123].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [118]
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Nasiri, H., Farahani, S., Mozafar, M., Ghiasi, Y., Fard, A. M., Naseri, N., Khodadadi, A., Asl, A. S., Mirzapour, M., Hamidi, H., et al. (2025) · Health Science Reports · doi:10.1002/hsr2.71671
“The Cox model defined the PHS as the weighted sum of the genotypes across the 31 SNPs, where each SNP's contribution was scaled by its estimated effect size [35].”
Prostate cancer risk prediction using polygenic hazard scores in Norwegian populationsPreprint
Morris, A. H., Akdeniz, B. C., Nakken, S., Shadrin, A. A., Dale, A. M., Andreassen, O. A., Eivind, H., Seibert, T. M., & Frei, O. (2026) · medRxiv · doi:10.64898/2026.01.07.26343583
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Preimplantation genetic testing for polygenic diseases: A novel paradigm in embryo selection
Jing, T., & Du, Y. (2026) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2026.102532
Kundu, P., Zhu, C., Huentelman, M. J., Deoni, S., Naymik, M., Taguinod, F., Both, M. D. D., Lewis, C. R., & Müller, H. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71279
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“Several predictors showed right-skewed distributions, including GDS, TMT-A, TMT-B, CSF tau measures, plasma biomarkers, the PHS, and florbetapir uptake, and were trans - formed using logarithmic or exp(− 0.5) functions.”
InfluentialSurvival Modeling in the Latent Space for Alzheimer’s Prognosis
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SuperAging is not the inverse of common-variant Alzheimer’s risk: evidence across genetic ancestries
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“The persistence of PRS associations after adjusting for APOE genotype further indicates that polygenic risk captures genetic influences on disease progression beyond the well-established APOE ε 4 associations[40-42].”
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Alzheimer’s disease: genetic background in the era of next-generation sequencing technologies
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“123 reported that higher PHS quartiles predict earlier Alzheimer’s disease onset and increased incidence and are strongly associated with neurodegeneration markers and pathological features.”
Metadata
- Authors
- Desikan, R. S., Fan, C. C., Wang, Y., Schork, A. J., Cabral, H. J., Cupples, L. A., Thompson, W. K., Besser, L., Kukull, W. A., Holland, D., Chen, C.-H., Brewer, J. B., Karow, D. S., Kauppi, K., Witoelar, A., Karch, C. M., Bonham, L. W., Yokoyama, J. S., Rosen, H. J., Miller, B. L., Dillon, W. P., Wilson, D. M., Hess, C. P., Pericak-Vance, M., Haines, J. L., Farrer, L. A., Mayeux, R., Hardy, J., Goate, A. M., Hyman, B. T., Schellenberg, G. D., McEvoy, L. K., Andreassen, O. A., & Dale, A. M.
- Affiliations
- University of California, San Francisco (US)
- University of California San Diego (US)
- Oslo University Hospital (NO)
- Boston University (US)
- Sankt Hans Hospital (DK)
- University of Washington (US)
- Washington University in St. Louis (US)
- Case Western Reserve University (US)
- Columbia University (US)
- UCL Queen Square Institute of Neurology (GB)
- Icahn School of Medicine at Mount Sinai (US)
- Massachusetts General Hospital (US)
- University of Pennsylvania (US)
- Corresponding author
- Desikan, Rahul S.
- Andreassen, Ole A.
- Dale, Anders M.
- ORCID
- Desikan, Rahul S.
- Fan, Chun Chieh
- Wang, Yunpeng
- Schork, Andrew J.
- Cabral, Howard J.
- Cupples, L. Adrienne
- Thompson, Wesley K.
- Kukull, Walter A.
- Holland, Dominic
- Chen, Chi-Hua
- Kauppi, Karolina
- Witoelar, Aree
- Karch, Celeste M.
- Bonham, Luke W.
- Yokoyama, Jennifer S.
- Miller, Bruce L.
- Dillon, William P.
- Wilson, David M.
- Hess, Christopher P.
- Haines, Jonathan L.
- Farrer, Lindsay A.
- Mayeux, Richard
- Hardy, John
- Goate, Alison M.
- Hyman, Bradley T.
- Schellenberg, Gerard D.
- McEvoy, Linda K.
- Andreassen, Ole A.
- Dale, Anders M.
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-03-21
- Volume
- 14
- Issue
- 3
- Pages
- e1002258
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC5360219
- OpenAlex
- W2600084629
- Cited by
- 395
- References
- 36
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 39 · 2023: 35 · 2022: 44 · 2021: 64 · 2020: 43 · 2019: 66 · 2018: 44 · 2017: 19
- FWCI
- 34.82
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-03-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Columbia Academic Commons (Columbia University)
- Funders
- National Institutes of Health (NIH-AG046374, K01AG049152, R01MH100351)
- National Alzheimer's Coordinating Center
- Radiological Society of North America
- Foundation of the American Society of Neuroradiology
- Norges Forskningsråd ((#213837, #225989, #223273, #237250/EU JPND)
- South East Norway Health Authority (2013-123)
- Norske Kvinners Sanitetsforening
- KG Jebsen Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, polygenic hazard score, genetic risk prediction, age of onset, Cox proportional hazards model, neurofibrillary tangles, neuritic plaques, entorhinal cortex atrophy, amygdala atrophy, hippocampal atrophy, APOE ε4, APOE ε2
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, United States, Geriatric Assessment, Multifactorial Inheritance, Polymorphism, Single Nucleotide
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