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Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years

BACKGROUND: In order to utilize polygenic risk scores (PRSs) for Alzheimer’s disease (AD) in a meaningful way, influential factors (i.e. training set) and prediction across groups such as APOE e4 (APOE4) genotype as well as associations to dementia-related biomarkers should be explored. Therefore, w...

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Autores principales: Stocker, Hannah, Trares, Kira, Beyer, Léon, Perna, Laura, Rujescu, Dan, Holleczek, Bernd, Beyreuther, Konrad, Gerwert, Klaus, Schöttker, Ben, Brenner, Hermann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10386275/
https://www.ncbi.nlm.nih.gov/pubmed/37516890
http://dx.doi.org/10.1186/s13195-023-01277-8
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author Stocker, Hannah
Trares, Kira
Beyer, Léon
Perna, Laura
Rujescu, Dan
Holleczek, Bernd
Beyreuther, Konrad
Gerwert, Klaus
Schöttker, Ben
Brenner, Hermann
author_facet Stocker, Hannah
Trares, Kira
Beyer, Léon
Perna, Laura
Rujescu, Dan
Holleczek, Bernd
Beyreuther, Konrad
Gerwert, Klaus
Schöttker, Ben
Brenner, Hermann
author_sort Stocker, Hannah
collection PubMed
description BACKGROUND: In order to utilize polygenic risk scores (PRSs) for Alzheimer’s disease (AD) in a meaningful way, influential factors (i.e. training set) and prediction across groups such as APOE e4 (APOE4) genotype as well as associations to dementia-related biomarkers should be explored. Therefore, we examined the association of APOE4 and various PRSs, based on training sets that utilized differing AD definitions, with incident AD and all-cause dementia (ACD) within 17 years, and with levels of phosphorylated tau181 (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) in blood. Secondarily, effect modification by APOE4 status and sex was examined. METHODS: In this prospective, population-based cohort study and nested case–control study, 9,940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed for up to 17 years. Participants were included in this study if dementia status and genetic data were available. A subsample of participants additionally had measurements of P-tau181, NfL, and GFAP obtained from blood samples. Cox and logistic regression analyses were used to assess the association of genetic risk (APOE genotype and PRS(noAPOE)) with incident ACD/AD and log-transformed blood levels of P-tau181, NfL, and GFAP. RESULTS: Five thousand seven hundred sixty-five participants (54% female, aged 50-75years at baseline) were included in this study, of whom 464 received an all-cause dementia diagnosis within 17 years. The PRSs were not more predictive of dementia than APOE4. An APOE4 specific relationship was apparent with PRSs only exhibiting associations to dementia among APOE4 carriers. In the nested case–control study including biomarkers (n = 712), APOE4 status and polygenic risk were significantly associated to levels of GFAP in blood. CONCLUSIONS: The use of PRSs may be beneficial for increased precision in risk estimates among APOE4 carriers. While APOE4 may play a crucial etiological role in initial disease processes such as Aβ deposition, the PRS may be an indicator of further disease drivers as well as astrocyte activation. Further research is necessary to confirm these findings, especially the association to GFAP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01277-8.
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spelling pubmed-103862752023-07-30 Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years Stocker, Hannah Trares, Kira Beyer, Léon Perna, Laura Rujescu, Dan Holleczek, Bernd Beyreuther, Konrad Gerwert, Klaus Schöttker, Ben Brenner, Hermann Alzheimers Res Ther Research BACKGROUND: In order to utilize polygenic risk scores (PRSs) for Alzheimer’s disease (AD) in a meaningful way, influential factors (i.e. training set) and prediction across groups such as APOE e4 (APOE4) genotype as well as associations to dementia-related biomarkers should be explored. Therefore, we examined the association of APOE4 and various PRSs, based on training sets that utilized differing AD definitions, with incident AD and all-cause dementia (ACD) within 17 years, and with levels of phosphorylated tau181 (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) in blood. Secondarily, effect modification by APOE4 status and sex was examined. METHODS: In this prospective, population-based cohort study and nested case–control study, 9,940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed for up to 17 years. Participants were included in this study if dementia status and genetic data were available. A subsample of participants additionally had measurements of P-tau181, NfL, and GFAP obtained from blood samples. Cox and logistic regression analyses were used to assess the association of genetic risk (APOE genotype and PRS(noAPOE)) with incident ACD/AD and log-transformed blood levels of P-tau181, NfL, and GFAP. RESULTS: Five thousand seven hundred sixty-five participants (54% female, aged 50-75years at baseline) were included in this study, of whom 464 received an all-cause dementia diagnosis within 17 years. The PRSs were not more predictive of dementia than APOE4. An APOE4 specific relationship was apparent with PRSs only exhibiting associations to dementia among APOE4 carriers. In the nested case–control study including biomarkers (n = 712), APOE4 status and polygenic risk were significantly associated to levels of GFAP in blood. CONCLUSIONS: The use of PRSs may be beneficial for increased precision in risk estimates among APOE4 carriers. While APOE4 may play a crucial etiological role in initial disease processes such as Aβ deposition, the PRS may be an indicator of further disease drivers as well as astrocyte activation. Further research is necessary to confirm these findings, especially the association to GFAP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01277-8. BioMed Central 2023-07-29 /pmc/articles/PMC10386275/ /pubmed/37516890 http://dx.doi.org/10.1186/s13195-023-01277-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Stocker, Hannah
Trares, Kira
Beyer, Léon
Perna, Laura
Rujescu, Dan
Holleczek, Bernd
Beyreuther, Konrad
Gerwert, Klaus
Schöttker, Ben
Brenner, Hermann
Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
title Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
title_full Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
title_fullStr Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
title_full_unstemmed Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
title_short Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
title_sort alzheimer’s polygenic risk scores, apoe, alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10386275/
https://www.ncbi.nlm.nih.gov/pubmed/37516890
http://dx.doi.org/10.1186/s13195-023-01277-8
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