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

Article type: Research Article

Authors: Chouraki, Vincent^{a; b; *} | Reitz, Christiane^c | Maury, Fleur^d | Bis, Joshua C.^e | Bellenguez, Celine^d | Yu, Lei^f | Jakobsdottir, Johanna^g | Mukherjee, Shubhabrata^e | Adams, Hieab H.^h | Choi, Seung Hoanⁱ | Larson, Eric B.^{e; j} | Fitzpatrick, Annette^e | Uitterlinden, Andre G.^h | de Jager, Philip L.^k | Hofman, Albert^h | Gudnason, Vilmundur^{g; l} | Vardarajan, Badri^c | Ibrahim-Verbaas, Carla^h | van der Lee, Sven J.^h | Lopez, Oscar^m | Dartigues, Jean-Françoisⁿ | Berr, Claudine^o | Amouyel, Philippe^d | Bennett, David A.^f | van Duijn, Cornelia^h | DeStefano, Anita L.ⁱ | Launer, Lenore J.^p | Ikram, M. Arfan^h | Crane, Paul K.^{e; j} | Lambert, Jean-Charles^d | Mayeux, Richard^c | Seshadri, Sudha^{a; b} | for the International Genomics of Alzheimer’s Project

Affiliations: [a] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [b] The Framingham Heart Study, Framingham, MA, USA | [c] Columbia University, New York, NY, USA | [d] 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 | [e] University of Washington, Seattle, WA, USA | [f] Rush Alzheimer’s Disease Center, Chicago, IL, USA | [g] Icelandic Heart Association, Kopavogur, Iceland | [h] Erasmus Medical Center, Rotterdam, The Netherlands | [i] Boston University School of Public Health, Boston, MA, USA | [j] Group Health Research Institute, Seattle, WA, USA | [k] Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, MA, USA | [l] Faculty of Medicine, University of Iceland, Reykjavik, Iceland | [m] Alzheimer’s Disease Research Center, Departments of Neurology, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [n] Inserm U1219, Bordeaux Population Health, University of Bordeaux, Bordeaux, France | [o] Inserm U1061 ‘Neuropsychiatry: epidemiological and clinical research’, Université de Montpellier, Monpellier, France | [p] National Institute on Aging, Bethesda, MD, USA

Correspondence: [*] Correspondence to: Vincent Chouraki, MD, PhD, Department of Neurology/The Framingham Study, Boston University School of Medicine, 72 East Concord Street B-601, 02118, Boston, MA, USA. Tel.: +1 617 638 8069; Email: vchourak@bu.edu.

Abstract: 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 ɛ4. 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 ɛ4 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 ɛ4, 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 ɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

Keywords: Alzheimer’s disease, clinical utility, cohort studies, genetic risk score, IGAP, meta-analysis, risk prediction

DOI: 10.3233/JAD-150749

Journal: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 921-932, 2016