Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer’s disease
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Le résumé fourni par la source
Summary The current demand for early intervention, prevention, and treatment of late onset Alzheimer’s disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE- ε 4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE- ε 4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE- ε 4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE- ε 4 genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE- ε 4 . Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Serum proteomics reveals <i>APOE</i> dependent and independent protein signatures in Alzheimer’s disease
- Date Crossref
- 09/11/2023
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Icelandic Heart Association pays non établi dans la noticeOrganisation à but non lucratif
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University of Iceland pays non établi dans la noticeUniversité ou école supérieure
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Emory University Department of Neurology pays non établi dans la noticeUniversité ou école supérieure
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Alzheimer’s Disease Neuroimaging Initiative pays non établi dans la noticeOrganisation à but non lucratif
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Universitat Internacional de Catalunya pays non établi dans la noticeUniversité ou école supérieure
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Fundació ACE pays non établi dans la noticeInstitution
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Instituto de Salud Carlos III pays non établi dans la noticeOrganisme public
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Biomedical Research Networking Center on Neurodegenerative Diseases pays non établi dans la noticeStructure de recherche
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Novartis (United States) pays non établi dans la noticeEntreprise
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Genomics Institute of the Novartis Research Foundation pays non établi dans la noticeStructure de recherche
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National Institute on Aging pays non établi dans la noticeStructure de recherche
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Faculty of Medicine pays non établi dans la noticeUniversité ou école supérieure
Icelandic Heart Association, University of Iceland et Department of Neurology — Emory University, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.