Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer’s Disease
Open accessAbstract
Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI = [1.13-1.21] per standard deviation increase in GRS; p-value = 2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex = 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.
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PRS incorporating only genome-wide significant SNPs show only a modest improvement in disease prediction over known risk factors such as APOEε4, age, and sex.
“PRS incorporating only genome-wide significant SNPs have showed only a modest improvement in disease prediction over known risk factors such as APOEε4, age, and sex [119–121].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [120]
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- Authors
- Chouraki, V., for the International Genomics of Alzheimer’s Project, Reitz, C., Maury, F., Bis, J. C., Bellenguez, C., Yu, L., Jakobsdottir, J., Mukherjee, S., Adams, H. H., Choi, S. H., Larson, E. B., Fitzpatrick, A., Uitterlinden, A. G., de Jager, P. L., Hofman, A., Gudnason, V., Vardarajan, B., Ibrahim-Verbaas, C., van der Lee, S. J., Lopez, O., Dartigues, J.-F., Berr, C., Amouyel, P., Bennett, D. A., van Duijn, C., DeStefano, A. L., Launer, L. J., Ikram, M. A., Crane, P. K., Lambert, J.-C., Mayeux, R., & Seshadri, S.
- Affiliations
- Boston University (US)
- Columbia University (US)
- Inserm (FR)
- Lille University, Inserm, Lille University Hospital, Institut Pasteur de Lille, U1167 - RID-AGE - Risk factors and molecular determinants of aging-related diseases; Labex Distalz, Lille, France
- Icelandic Heart Association (IS)
- Icelandic Heart Association, Kopavogur, Iceland
- University of Washington (US)
- Kaiser Permanente Washington Health Research Institute (US)
- Erasmus Medical Center, Rotterdam, The Netherlands
- Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, MA, USA
- University of Iceland (IS)
- Erasmus MC (NL)
- Alzheimer’s Disease Research Center, Departments of Neurology, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Université de Bordeaux (FR)
- Rush University Medical Center (US)
- National Institutes of Health (US)
- Corresponding author
- Chouraki, Vincent
- ORCID
- Chouraki, Vincent
- Bis, Joshua C.
- Yu, Lei
- Mukherjee, Shubhabrata
- Adams, Hieab H.
- Choi, Seung Hoan
- Larson, Eric B.
- Gudnason, Vilmundur
- Vardarajan, Badri
- Dartigues, Jean-François
- Berr, Claudine
- Amouyel, Philippe
- Bennett, David A.
- DeStefano, Anita L.
- Launer, Lenore J.
- Ikram, M. Arfan
- Crane, Paul K.
- Lambert, Jean-Charles
- Mayeux, Richard
- Seshadri, Sudha
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2016-08-03
- Volume
- 53
- Issue
- 3
- Pages
- 921-932
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC5036102
- OpenAlex
- W2465169012
- Cited by
- 98
- References
- 7
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 10 · 2023: 7 · 2022: 9 · 2021: 15 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 7 · 2016: 1
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health (n01hc085082-026, n01hc085081-021, n01ag12100-57-0-2, n01hc085079-024, 1r01hl120393-01a1, n01hc085083-027, n01hc085080-026, UL1TR000124, n01hc085086-022, n01hc25195-41-0-1, n01hc55222-0-0-0)
- Medical Research Council (MR/L023784/2, MR/L501517/1, MR/L010305/1, MR/K013041/1, MR/L023784/1)
- National Institute on Aging (R01AG017917, P30AG010129, R01AG030146, U01AG049505, R01AG037212, N01-AG012100, P50AG005133, U01AG006781, RF1AG015473, R01AG020098, R01AG015819, P30AG010161, R01AG054076, R01AG041797, R01AG023629, R01AG033193, RF1AG015819, R01AG015928, R01AG027058, R01AG008122, U24AG056270, U24AG021886)
- National Heart, Lung, and Blood Institute (N01 HC085086, N01 HC085079, R01-HL120393, N01 HC085083, HHSN268201500001I, N01 HC085080, R01HL087652, R01HL103612, HHSN 268200800007C, HHSN268201500001C, N01-HC-025195, HHSN268201200036C, N01HC085082, R01HL105756, U01HL080295, N01 HC055222, N01 HC085081)
- National Human Genome Research Institute (U01HG004610, U01HG006375)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, polygenic risk score
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Educational Status, Female, Genetic Testing, Humans, Male, Neuropsychological Tests, Predictive Value of Tests, Psychiatric Status Rating Scales, Risk Factors, Cohort Studies, Proportional Hazards Models, Risk Assessment, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Apolipoprotein E4, Genome-Wide Association Study
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