Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease

Vincent Chouraki, Christiane Reitz, Fleur Maury, Joshua C. Bis, Celine Bellenguez, Lei Yu, Johanna Jakobsdottir, Shubhabrata Mukherjee, Hieab H. Adams, Seung Hoan Choi, Eric B. Larson, Annette Fitzpatrick, Andre G. Uitterlinden, Philip L. De Jager, Albert Hofman, Vilmundur Gudnason, Badri Vardarajan, Carla Ibrahim-Verbaas, Sven J. Van Der Lee, Oscar LopezJean François Dartigues, Claudine Berr, Philippe Amouyel, David A. Bennett, Cornelia Van Duijn, Anita L. Destefano, Lenore J. Launer, M. Arfan Ikram, Paul K. Crane, Jean Charles Lambert, Richard Mayeux, Sudha Seshadri

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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 APOE ϵ4. 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 APOE ϵ4 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, APOE ϵ4, 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 APOE ϵ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

Original languageEnglish (US)
Pages (from-to)921-932
Number of pages12
JournalJournal of Alzheimer's Disease
Issue number3
StatePublished - 2016
Externally publishedYes


  • Alzheimer's disease
  • IGAP
  • clinical utility
  • cohort studies
  • genetic risk score
  • meta-analysis
  • risk prediction

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


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