title: Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.
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 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.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The Framingham Heart Study, Framingham, MA, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chouraki
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.affiliation: 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.
authors.forename: Fleur
authors.initials: F
authors.lastname: Maury
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: 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.
authors.forename: Celine
authors.initials: C
authors.lastname: Bellenguez
authors.affiliation: Rush Alzheimer's Disease Center, Chicago, IL, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Jakobsdottir
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Hieab H
authors.initials: HH
authors.lastname: Adams
authors.affiliation: Boston University School of Public Health, Boston, MA, USA.
authors.forename: Seung Hoan
authors.initials: SH
authors.lastname: Choi
authors.affiliation: University of Washington, Seattle, WA, USA.|Group Health Research Institute, Seattle, WA, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Fitzpatrick
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, MA, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: de Jager
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: Ibrahim-Verbaas
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Sven J
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Alzheimer's Disease Research Center, Departments of Neurology, Psychiatry and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Lopez
authors.affiliation: Inserm U1219, Bordeaux Population Health, University of Bordeaux, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: Inserm U1061 'Neuropsychiatry: epidemiological and clinical research', Université de Montpellier, Monpellier, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Berr
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: Rush Alzheimer's Disease Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.affiliation: Boston University School of Public Health, Boston, MA, USA.
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.affiliation: National Institute on Aging, Bethesda, MD, USA.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: University of Washington, Seattle, WA, USA.|Group Health Research Institute, Seattle, WA, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: 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.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The Framingham Heart Study, Framingham, MA, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D015331:Cohort Studies; D004522:Educational Status; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D053327:Apolipoprotein E4
keywords: Alzheimer’s disease; IGAP; clinical utility; cohort studies; genetic risk score; meta-analysis; risk prediction