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

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Frick, Elisabet A., Emilsson, Valur, Jonmundsson, Thorarinn, Steindorsdottir, Anna E., Johnson, Erik C. B., Puerta, Raquel, Dammer, Eric B., Shantaraman, Anantharaman +16 more·2023·medRxiv
DOI 10.1101/2023.11.08.23298251PMC PMC10659486
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Abstract

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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  • Among the most upregulated DEGs, higher amounts of MMP3, IBSP, or TAGLN in the brain have been linked to increased risk of AD.

    “Among the most upregulated DEGs, higher amounts of MMP3 (52), IBSP (53), or TAGLN (54) in the brain have been linked to increased risk of AD.”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [53]

    The Results section on Mendelian randomization reports that higher IBSP was associated with increased risk of late-onset AD in serum-based analyses. It does not establish that higher IBSP amounts in the brain are linked to that risk; the brain-proteome comparison does not identify IBSP as such a finding. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Frick, E. A., Emilsson, V., Jonmundsson, T., Steindorsdottir, A. E., Johnson, E. C. B., Puerta, R., Dammer, E. B., Shantaraman, A., Cano, A., Boada, M., Valero, S., García-González, P., Gudmundsson, E. F., Gudjonsson, A., Loureiro, J. J., Orth, A. P., Seyfried, N. T., Levey, A. I., Ruiz, A., Aspelund, T., Jennings, L. L., Launer, L. J., Gudmundsdottir, V., & Gudnason, V.
Affiliations
  • Icelandic Heart Association (IS)
  • University of Iceland (IS)
  • Emory University (US)
  • Universitat Internacional de Catalunya (ES)
  • Instituto de Salud Carlos III (ES)
  • National Institutes of Health (US)
Corresponding author
Gudnason, Vilmundur
ORCID
Venue
medRxiv
Publisher
openRxiv
Published
2023-11-09
DOI
10.1101/2023.11.08.23298251
PMC
PMC10659486
OpenAlex
W4388519437
Cited by
3
References
13
Citations by year
2025: 1 · 2024: 2
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Agentschap Innoveren en Ondernemen (Nº PR067/21)
  • EU Joint Programme – Neurodegenerative Disease Research (AC19/00097)
  • European Federation of Pharmaceutical Industries and Associations (115985, 115975)
  • European Commission (115985, PMP22/00022, 115975)
  • Deutsche Forschungsgemeinschaft
  • Ministerio de Ciencia e Innovación (PID2019, PID2019-106625RB-I00, CB06/05/2004, PID2021-123462OB-I00, PID2021-122473OA-I00)
  • Hjartavernd (HHSN271201200022C, N01-AG-1-2100)
  • Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CB18/05/00010, CB06/05/2004)
  • Grifols
  • National Institutes of Health (n01ag12100-57-0-2, HHSN271201200022C, N01-AG-1-2100, 1r01ag065596-01a1, 00097)
  • Instituto de Salud Carlos III (PI16/, PI22/00258, PI13/02434, AC19/00097, PI19/01301, PI16/01861, PI22/01403, PI19/01240, PMP22/00022, PI17/01474, PI19/00335, CD22/00125)
  • European Regional Development Fund
  • National Institute on Aging (1R01AG065596-01A1, N01-AG12100, 1R01AG065596, U01AG061357, K08AG068604, HHSN271201200022C, P30AG066511)
  • NextGenerationEU
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
late-onset Alzheimer's disease, serum proteomics, APOE ε4, circulating biomarkers, proteomic signatures, ARL2, S100A13, IRF6, Mendelian randomization, cerebrospinal fluid protein, brain gene expression, older adults

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