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

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 p...

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Autores principales: Euesden, Jack, Gowrisankar, Sivakumar, Qu, Angela Xiaoyan, St. Jean, Pamela, Hughes, Arlene R., Pulford, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290959/
https://www.ncbi.nlm.nih.gov/pubmed/32370229
http://dx.doi.org/10.3390/genes11050501
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author Euesden, Jack
Gowrisankar, Sivakumar
Qu, Angela Xiaoyan
St. Jean, Pamela
Hughes, Arlene R.
Pulford, David J.
author_facet Euesden, Jack
Gowrisankar, Sivakumar
Qu, Angela Xiaoyan
St. Jean, Pamela
Hughes, Arlene R.
Pulford, David J.
author_sort Euesden, Jack
collection PubMed
description 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.
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spelling pubmed-72909592020-06-19 Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting Euesden, Jack Gowrisankar, Sivakumar Qu, Angela Xiaoyan St. Jean, Pamela Hughes, Arlene R. Pulford, David J. Genes (Basel) Brief Report 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. MDPI 2020-05-02 /pmc/articles/PMC7290959/ /pubmed/32370229 http://dx.doi.org/10.3390/genes11050501 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Euesden, Jack
Gowrisankar, Sivakumar
Qu, Angela Xiaoyan
St. Jean, Pamela
Hughes, Arlene R.
Pulford, David J.
Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting
title Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting
title_full Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting
title_fullStr Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting
title_full_unstemmed Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting
title_short Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting
title_sort cognitive decline in alzheimer’s disease: limited clinical utility for gwas or polygenic risk scores in a clinical trial setting
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290959/
https://www.ncbi.nlm.nih.gov/pubmed/32370229
http://dx.doi.org/10.3390/genes11050501
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