Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer’s disease

• Type of Material: Article
• Authors: Elisabet A. Frick, Icelandic Heart Association; Valur Emilsson, University of Iceland; Thorarinn Jonmundsson, University of Iceland; Anna E. Steindorsdottir, University of Iceland; Erik Johnson, Emory University; Raquel Puerta, Universitat Internacional de Catalunya; Eric B Dammer, Emory University; Ananth Shantaraman, Emory University; Amanda Cano, Universitat Internacional de Catalunya; Mercè Boada, Universitat Internacional de Catalunya; Sergi Valero, Universitat Internacional de Catalunya; Pablo García-González, Universitat Internacional de Catalunya; Elias F. Gudmundsson, Icelandic Heart Association; Alexander Gudjonsson, Icelandic Heart Association; Joseph J. Loureiro, Novartis Biomedical Research; Anthony P. Orth, Novartic Biomedical Research; Nicholas Seyfried, Emory University; Allan I Levey, Emory University; Agustin Ruiz, Universitat Internacional de Catalunya; Thor Aspelund, University of Iceland; Lor L. Jennings, Novartis Biomedical Research; Lenore J. Launer, National Institute of Aging; Valborg Gudmundsdottir, University of Iceland; Vilmundur Gudnason, University of Iceland
• Language: English
• Date: 2023-11-09
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
• Final Published Version (URL): https://doi.org/10.1101/2023.11.08.23298251
• Title of Journal or Parent Work: medRxiv
• Start Page: 23298251
• Grant/Funding Information: The protein measurements in AGES were supported by Novartis Biomedical Research. The National Institute on Aging (NIA) contracts N01-AG-12100 and HHSN271201200022C for V.G. financed the study. IHA received a grant from Althingi (the Icelandic Parliament), V.G. received funding from the NIA (1R01AG065596-01A1) and E.J. from the NIA (1K08AG068604). A.I.L was also funded from the NIA (P30AG066511 and U01AG061357). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Genome Research @ Ace Alzheimer Center Barcelona project (GR@ACE) is supported by Grifols SA, Fundación bancaria ‘La Caixa’, Ace Alzheimer Center Barcelona and CIBERNED. Ace Alzheimer Center Barcelona is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The FACEHBI study is supported by funds from Ace Alzheimer Center Barcelona, Grifols, Life Molecular Imaging, Araclon Biotech, Alkahest, Laboratorio de análisis Echevarne and IrsiCaixa. Authors acknowledge the support of the Spanish Ministry of Science and Innovation, Proyectos de Generación de Conocimiento grants PID2021-122473OA-I00, PID2021-123462OB-I00 and PID2019-106625RB-I00. ISCIII, Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER “Una manera de hacer Europa”) grants PI13/02434, PI16/01861, PI17/01474, PI19/00335, PI19/01240, PI19/01301, PI22/01403, PI22/00258 and the ISCIII national grant PMP22/00022, funded by the European Union (NextGenerationEU). The support of CIBERNED (ISCIII) under the grants CB06/05/2004 and CB18/05/00010. The support from the ADAPTED and MOPEAD projects, European Union/EFPIA Innovative Medicines Initiative Joint (grant numbers 115975 and 115985, respectively); from PREADAPT project, Joint Program for Neurodegenerative Diseases (JPND) grant N° AC19/00097; from HARPONE project, Agency for Innovation and Entrepreneurship (VLAIO) grant N° PR067/21 and Janssen. DESCARTES project is funded by German Research Foundation (DFG). Amanda Cano received support from the ISCIII under the grant Sara Borrell (CD22/00125).
• Keywords: high-throughput proteomic measurements; late onset Alzheimer’s disease (LOAD)
• Research Categories: Biology, Neuroscience; Health Sciences, Epidemiology

Abstract

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-ε4 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-ε4 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-ε4 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-ε4 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-ε4. 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.