{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T22:37:27Z","timestamp":1789252647413,"version":"build-2803163510"},"reference-count":10,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,2]],"date-time":"2020-05-02T00:00:00Z","timestamp":1588377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction: Alzheimer\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/genes11050501","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T06:41:20Z","timestamp":1588660880000},"page":"501","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cognitive Decline in Alzheimer\u2019s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6790-1925","authenticated-orcid":false,"given":"Jack","family":"Euesden","sequence":"first","affiliation":[{"name":"GlaxoSmithKline Medicines R&amp;D, Stevenage, Hertfordshire SG1 2NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakumar","family":"Gowrisankar","sequence":"additional","affiliation":[{"name":"Parexel International, 2520 Meridian Parkway, Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela Xiaoyan","family":"Qu","sequence":"additional","affiliation":[{"name":"Parexel International, 2520 Meridian Parkway, Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"St. Jean","sequence":"additional","affiliation":[{"name":"Parexel International, 2520 Meridian Parkway, Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene R.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Parexel International, 2520 Meridian Parkway, Durham, NC 27713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Pulford","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Medicines R&amp;D, Stevenage, Hertfordshire SG1 2NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer\u2019s disease","volume":"368","author":"Guerreiro","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.ajhg.2008.10.008","article-title":"Genome-wide association analysis reveals putative Alzheimer\u2019s disease susceptibility loci in addition to APOE","volume":"83","author":"Bertram","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1212\/WNL.43.8.1467","article-title":"Association of apolipoprotein E allele \u03f54 with late-onset familial and sporadic Alzheimer\u2019s disease","volume":"43","author":"Saunders","year":"1993","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1093\/brain\/awv231","article-title":"GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer\u2019s disease implicates microglial activation gene IL1RAP","volume":"138","author":"Ramanan","year":"2015","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"745","DOI":"10.3233\/JAD-170834","article-title":"Assessment of the Genetic Architecture of Alzheimer\u2019s Disease Risk in Rate of Memory Decline","volume":"62","author":"Fernandez","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"592","DOI":"10.2174\/156720511796391935","article-title":"Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer\u2019s disease: Two phase 3 studies","volume":"8","author":"Harrington","year":"2011","journal-title":"Curr. Alzheimer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/ng.2802","article-title":"Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer\u2019s disease","volume":"45","author":"Lambert","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1093\/bioinformatics\/btu848","article-title":"PRSice: Polygenic Risk Score software","volume":"31","author":"Euesden","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","article-title":"GCTA: A tool for genome-wide complex trait analysis","volume":"88","author":"Yang","year":"2011","journal-title":"Am. J. Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/501\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:25:13Z","timestamp":1760361913000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/501"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,2]]},"references-count":10,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["genes11050501"],"URL":"https:\/\/doi.org\/10.3390\/genes11050501","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,2]]}}}