APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease

Background Aggregation of amyloid beta into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) epsilon 4 genotype plays a major role. We aimed to identify...

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Autores: Konijnenberg, E, Tijms, BM, Gobom, J, Dobricic, V, Bos, I, Vos, S, Tsolaki, M, Verhey, F, Popp, J, Martinez-Lage, P, Vandenberghe, R, Lleo, A, Frolich, L, Lovestone, S, Streffer, J, Bertram, L, Blennow, K, Teunissen, CE, Veerhuis, R, Smit, AB, Scheltens, P, Zetterberg, H, Visser, PJ
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2020
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositório:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p1889
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1889
Access Level:Acceso aberto
Palavra-chave:Amyloid aggregation
APOE genotype
CSF proteomics
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spelling APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's diseaseKonijnenberg, ETijms, BMGobom, JDobricic, VBos, IVos, STsolaki, MVerhey, FPopp, JMartinez-Lage, PVandenberghe, RLleo, AFrolich, LLovestone, SStreffer, JBertram, LBlennow, KTeunissen, CEVeerhuis, RSmit, ABScheltens, PZetterberg, HVisser, PJAmyloid aggregationAPOE genotypeCSF proteomicsBackground Aggregation of amyloid beta into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) epsilon 4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid beta aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE epsilon 4 genotype. Methods We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE epsilon 4 carriers, average age 75 +/- 7 years) against 60 controls with normal CSF amyloid beta, normal cognition, and no APOE epsilon 4 allele (average age 75 +/- 6 years). Results One hundred twenty-nine proteins (53%) were associated with aggregated amyloid beta. APOE epsilon 4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE epsilon 4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. Conclusions These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.BMC2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1889Alzheimers Research & TherapyISSN: 17589193reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p18892026-06-14T12:41:47Z
dc.title.none.fl_str_mv APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
title APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
spellingShingle APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
Konijnenberg, E
Amyloid aggregation
APOE genotype
CSF proteomics
title_short APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
title_full APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
title_fullStr APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
title_full_unstemmed APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
title_sort APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
dc.creator.none.fl_str_mv Konijnenberg, E
Tijms, BM
Gobom, J
Dobricic, V
Bos, I
Vos, S
Tsolaki, M
Verhey, F
Popp, J
Martinez-Lage, P
Vandenberghe, R
Lleo, A
Frolich, L
Lovestone, S
Streffer, J
Bertram, L
Blennow, K
Teunissen, CE
Veerhuis, R
Smit, AB
Scheltens, P
Zetterberg, H
Visser, PJ
author Konijnenberg, E
author_facet Konijnenberg, E
Tijms, BM
Gobom, J
Dobricic, V
Bos, I
Vos, S
Tsolaki, M
Verhey, F
Popp, J
Martinez-Lage, P
Vandenberghe, R
Lleo, A
Frolich, L
Lovestone, S
Streffer, J
Bertram, L
Blennow, K
Teunissen, CE
Veerhuis, R
Smit, AB
Scheltens, P
Zetterberg, H
Visser, PJ
author_role author
author2 Tijms, BM
Gobom, J
Dobricic, V
Bos, I
Vos, S
Tsolaki, M
Verhey, F
Popp, J
Martinez-Lage, P
Vandenberghe, R
Lleo, A
Frolich, L
Lovestone, S
Streffer, J
Bertram, L
Blennow, K
Teunissen, CE
Veerhuis, R
Smit, AB
Scheltens, P
Zetterberg, H
Visser, PJ
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Amyloid aggregation
APOE genotype
CSF proteomics
topic Amyloid aggregation
APOE genotype
CSF proteomics
description Background Aggregation of amyloid beta into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) epsilon 4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid beta aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE epsilon 4 genotype. Methods We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE epsilon 4 carriers, average age 75 +/- 7 years) against 60 controls with normal CSF amyloid beta, normal cognition, and no APOE epsilon 4 allele (average age 75 +/- 6 years). Results One hundred twenty-nine proteins (53%) were associated with aggregated amyloid beta. APOE epsilon 4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE epsilon 4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. Conclusions These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1889
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1889
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Alzheimers Research & Therapy
ISSN: 17589193
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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