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Brief Report

Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting

1
GlaxoSmithKline Medicines R&D, Stevenage, Hertfordshire SG1 2NY, UK
2
Parexel International, 2520 Meridian Parkway, Durham, NC 27713, USA
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Author to whom correspondence should be addressed.
Genes 2020, 11(5), 501; https://doi.org/10.3390/genes11050501
Received: 5 March 2020 / Revised: 21 April 2020 / Accepted: 28 April 2020 / Published: 2 May 2020
(This article belongs to the Special Issue Genetics and Genomics of Alzheimer’s Disease)
Introduction: Alzheimer’s disease (AD) is a progressive and irreversible neurological disease. The genetics and molecular mechanisms underpinning differential cognitive decline in AD are not well understood; the genetics of AD risk have been studied far more assiduously. Materials and Methods: Two phase III clinical trials measuring cognitive decline over 48 weeks using Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog, n = 2060) and Clinical Dementia Rating-Sum of Boxes (CDR-SB, n = 1996) were retrospectively genotyped. A Genome-Wide Association Study (GWAS) was performed to identify and replicate genetic variants associated with cognitive decline. The relationship between polygenic risk score (PRS) and cognitive decline was tested to investigate the predictive power of aggregating many variants of individually small effect. Results: No loci met candidate gene or genome-wide significance. PRS explained a very small percentage of variance in rates of cognitive decline (ADAS-cog: 0.54%). Conclusions: These results suggest that incorporating genetic information in the prediction of cognitive decline in AD currently appears to have limited utility in clinical trials, consistent with small effect sizes estimated elsewhere. If AD progression is more heritable soon after disease onset, genetics may have more clinical utility. View Full-Text
Keywords: Alzheimer’s disease; Alzheimer’s disease late onset; polymorphism; single nucleotide; genetic variation; dementia; apolipoprotein E4; risk factors; genome-wide association study Alzheimer’s disease; Alzheimer’s disease late onset; polymorphism; single nucleotide; genetic variation; dementia; apolipoprotein E4; risk factors; genome-wide association study
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MDPI and ACS Style

Euesden, J.; Gowrisankar, S.; Qu, A.X.; St. Jean, P.; Hughes, A.R.; Pulford, D.J. Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting. Genes 2020, 11, 501. https://doi.org/10.3390/genes11050501

AMA Style

Euesden J, Gowrisankar S, Qu AX, St. Jean P, Hughes AR, Pulford DJ. Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting. Genes. 2020; 11(5):501. https://doi.org/10.3390/genes11050501

Chicago/Turabian Style

Euesden, Jack, Sivakumar Gowrisankar, Angela X. Qu, Pamela St. Jean, Arlene R. Hughes, and David J. Pulford. 2020. "Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting" Genes 11, no. 5: 501. https://doi.org/10.3390/genes11050501

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