Abstract
The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor of Alzheimer’s disease (AD) but does not account for the entirety of genetic risk. Genetic risk scores (GRSs) incorporating additional genetic variants have been developed to determine the genetic risk for AD, yet there is no systematic review assessing the contribution of GRSs for AD beyond the effect of APOE ε4. The purpose of this systematic PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses)-based review was to summarize original research studies that have developed and validated a GRS for AD utilizing associated single nucleotide polymorphisms (SNPs). The PubMed and Web of Science databases were searched on April 6, 2018 and screening was completed on 2018 citations by two independent reviewers. Eighteen studies published between 2010 and 2018 were included in the review. All GRSs expressed significant associations or discrimination capability of AD when compared to clinically normal controls; however, GRS prediction of MCI to AD conversion was mixed. APOE ε4 status was more predictive of AD than the GRSs, although the GRSs did add to AD prediction accuracy beyond APOE ε4. GRSs might contribute to identifying genetic risk of AD beyond APOE. However, additional studies are warranted to assess the performance of GRSs in independent longitudinal cohorts.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and is a critical public health issue across the globe[1]
In stage 1, International Genomics of Alzheimer’s Project (IGAP) used genotyped and imputed data on 7,055,881 single nucleotide polymorphisms (SNPs) to meta-analyze four previously-published genome-wide association studies (GWASs) datasets consisting of 17,008 AD cases and 37,154 controls
Results were mixed in predicting mild cognitive impairment (MCI) to AD conversion and the Genetic risk scores (GRSs) were less predictive of AD than Apolipoprotein E (APOE) ε4 status
Summary
Alzheimer’s disease (AD) is the most common form of dementia and is a critical public health issue across the globe[1]. The strongest known genetic risk factor for AD is the ε4 allele of Apolipoprotein E (APOE ε4), but large-scale genome-wide association studies (GWASs) have identified additional genetic loci associated with AD4–7. The largest GWAS meta-analysis concerning AD to date (N = 74,046), The International Genomics of Alzheimer’s Project (IGAP), has confirmed at least 20 genetic loci in addition to APOE genotype to be associated with AD8. The IGAP is a large two-stage study based upon GWASs on individuals of European ancestry. In stage 1, IGAP used genotyped and imputed data on 7,055,881 single nucleotide polymorphisms (SNPs) to meta-analyze four previously-published GWAS datasets consisting of 17,008 AD cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8572 AD cases and 11,312 controls. A meta-analysis was performed combining results from stages 1 and 28
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