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Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults

BACKGROUND: Gene expression is dysregulated in Alzheimer’s disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset. METHODS: RNA was extracted and sequenced for 65 cognitiv...

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Autores principales: Luckett, Emma S., Zielonka, Magdalena, Kordjani, Amine, Schaeverbeke, Jolien, Adamczuk, Katarzyna, De Meyer, Steffi, Van Laere, Koen, Dupont, Patrick, Cleynen, Isabelle, Vandenberghe, Rik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337180/
https://www.ncbi.nlm.nih.gov/pubmed/37438770
http://dx.doi.org/10.1186/s13195-023-01242-5
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author Luckett, Emma S.
Zielonka, Magdalena
Kordjani, Amine
Schaeverbeke, Jolien
Adamczuk, Katarzyna
De Meyer, Steffi
Van Laere, Koen
Dupont, Patrick
Cleynen, Isabelle
Vandenberghe, Rik
author_facet Luckett, Emma S.
Zielonka, Magdalena
Kordjani, Amine
Schaeverbeke, Jolien
Adamczuk, Katarzyna
De Meyer, Steffi
Van Laere, Koen
Dupont, Patrick
Cleynen, Isabelle
Vandenberghe, Rik
author_sort Luckett, Emma S.
collection PubMed
description BACKGROUND: Gene expression is dysregulated in Alzheimer’s disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset. METHODS: RNA was extracted and sequenced for 65 cognitively healthy F-PACK participants (65 (56–80) years, 34 APOE4 non-carriers, 31 APOE4 carriers), at baseline and follow-up (interval: 5.0 (3.4–8.6) years). Participants received amyloid PET at both time points and amyloid rate of change derived. Accumulators were defined with rate of change ≥ 2.19 Centiloids. We performed differential gene expression and weighted gene co-expression network analysis to identify differentially expressed genes and networks of co-expressed genes, respectively, with respect to traits of interest (APOE4 status, amyloid accumulation (binary/continuous)), and amyloid positivity status, followed by Gene Ontology annotation. RESULTS: There were 166 significant differentially expressed genes at follow-up compared to baseline in APOE4 carriers only, whereas 12 significant differentially expressed genes were found only in APOE4 non-carriers, over time. Among the significant genes in APOE4 carriers, several had strong evidence for a pathogenic role in AD based on direct association scores generated from the DISQOVER platform: NGRN, IGF2, GMPR, CLDN5, SMIM24. Top enrichment terms showed upregulated mitochondrial and metabolic pathways, and an exacerbated upregulation of ribosomal pathways in APOE4 carriers compared to non-carriers. Similarly, there were 33 unique significant differentially expressed genes at follow-up compared to baseline in individuals classified as amyloid negative at baseline and positive at follow-up or amyloid positive at both time points and 32 unique significant differentially expressed genes over time in individuals amyloid negative at both time points. Among the significant genes in the first group, the top five with the highest direct association scores were as follows: RPL17-C18orf32, HSP90AA1, MBP, SIRPB1, and GRINA. Top enrichment terms included upregulated metabolism and focal adhesion pathways. Baseline and follow-up gene co-expression networks were separately built. Seventeen baseline co-expression modules were derived, with one significantly negatively associated with amyloid accumulator status (r(2) =  − 0.25, p = 0.046). This was enriched for proteasomal protein catabolic process and myeloid cell development. Thirty-two follow-up modules were derived, with two significantly associated with APOE4 status: one downregulated (r(2) =  − 0.27, p = 0.035) and one upregulated (r(2) = 0.26, p = 0.039) module. Top enrichment processes for the downregulated module included proteasomal protein catabolic process and myeloid cell homeostasis. Top enrichment processes for the upregulated module included cytoplasmic translation and rRNA processing. CONCLUSIONS: We show that there are longitudinal gene expression changes that implicate a disrupted immune system, protein removal, and metabolism in cognitively intact individuals who carry APOE4 or who accumulate in cortical amyloid. This provides insight into the pathophysiology of AD, whilst providing novel targets for drug and therapeutic development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01242-5.
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spelling pubmed-103371802023-07-13 Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults Luckett, Emma S. Zielonka, Magdalena Kordjani, Amine Schaeverbeke, Jolien Adamczuk, Katarzyna De Meyer, Steffi Van Laere, Koen Dupont, Patrick Cleynen, Isabelle Vandenberghe, Rik Alzheimers Res Ther Research BACKGROUND: Gene expression is dysregulated in Alzheimer’s disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset. METHODS: RNA was extracted and sequenced for 65 cognitively healthy F-PACK participants (65 (56–80) years, 34 APOE4 non-carriers, 31 APOE4 carriers), at baseline and follow-up (interval: 5.0 (3.4–8.6) years). Participants received amyloid PET at both time points and amyloid rate of change derived. Accumulators were defined with rate of change ≥ 2.19 Centiloids. We performed differential gene expression and weighted gene co-expression network analysis to identify differentially expressed genes and networks of co-expressed genes, respectively, with respect to traits of interest (APOE4 status, amyloid accumulation (binary/continuous)), and amyloid positivity status, followed by Gene Ontology annotation. RESULTS: There were 166 significant differentially expressed genes at follow-up compared to baseline in APOE4 carriers only, whereas 12 significant differentially expressed genes were found only in APOE4 non-carriers, over time. Among the significant genes in APOE4 carriers, several had strong evidence for a pathogenic role in AD based on direct association scores generated from the DISQOVER platform: NGRN, IGF2, GMPR, CLDN5, SMIM24. Top enrichment terms showed upregulated mitochondrial and metabolic pathways, and an exacerbated upregulation of ribosomal pathways in APOE4 carriers compared to non-carriers. Similarly, there were 33 unique significant differentially expressed genes at follow-up compared to baseline in individuals classified as amyloid negative at baseline and positive at follow-up or amyloid positive at both time points and 32 unique significant differentially expressed genes over time in individuals amyloid negative at both time points. Among the significant genes in the first group, the top five with the highest direct association scores were as follows: RPL17-C18orf32, HSP90AA1, MBP, SIRPB1, and GRINA. Top enrichment terms included upregulated metabolism and focal adhesion pathways. Baseline and follow-up gene co-expression networks were separately built. Seventeen baseline co-expression modules were derived, with one significantly negatively associated with amyloid accumulator status (r(2) =  − 0.25, p = 0.046). This was enriched for proteasomal protein catabolic process and myeloid cell development. Thirty-two follow-up modules were derived, with two significantly associated with APOE4 status: one downregulated (r(2) =  − 0.27, p = 0.035) and one upregulated (r(2) = 0.26, p = 0.039) module. Top enrichment processes for the downregulated module included proteasomal protein catabolic process and myeloid cell homeostasis. Top enrichment processes for the upregulated module included cytoplasmic translation and rRNA processing. CONCLUSIONS: We show that there are longitudinal gene expression changes that implicate a disrupted immune system, protein removal, and metabolism in cognitively intact individuals who carry APOE4 or who accumulate in cortical amyloid. This provides insight into the pathophysiology of AD, whilst providing novel targets for drug and therapeutic development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01242-5. BioMed Central 2023-07-12 /pmc/articles/PMC10337180/ /pubmed/37438770 http://dx.doi.org/10.1186/s13195-023-01242-5 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
Luckett, Emma S.
Zielonka, Magdalena
Kordjani, Amine
Schaeverbeke, Jolien
Adamczuk, Katarzyna
De Meyer, Steffi
Van Laere, Koen
Dupont, Patrick
Cleynen, Isabelle
Vandenberghe, Rik
Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
title Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
title_full Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
title_fullStr Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
title_full_unstemmed Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
title_short Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
title_sort longitudinal apoe4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337180/
https://www.ncbi.nlm.nih.gov/pubmed/37438770
http://dx.doi.org/10.1186/s13195-023-01242-5
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