Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease
A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.
Authors
- Vilmundur Guðnason (ORCID: https://orcid.org/0000-0001-5696-0084)
- Valborg Guðmundsdóttir (ORCID: https://orcid.org/0000-0002-7459-1603)
- Lori L. Jennings (ORCID: https://orcid.org/0000-0001-5130-8417)
- Agustı́n Ruiz (ORCID: https://orcid.org/0000-0003-2633-2495)
- Lenore J. Launer (ORCID: https://orcid.org/0000-0002-3238-7612)
- Nicholas T. Seyfried (ORCID: https://orcid.org/0000-0002-4507-624X)
- Allan I. Levey (ORCID: https://orcid.org/0000-0002-3153-502X)
- Joseph Loureiro (ORCID: https://orcid.org/0000-0001-7222-9160)
- Erik C. B. Johnson (ORCID: https://orcid.org/0000-0002-0604-2944)
- Rebecca Pitts (ORCID: https://orcid.org/0000-0003-4733-414X)
- Amanda C. Cano (ORCID: https://orcid.org/0000-0001-9567-4283)
- Anthony P. Orth (ORCID: https://orcid.org/0009-0005-9865-0494)
- Merçé Boada (ORCID: https://orcid.org/0000-0003-2617-3009)
- Eric B. Dammer (ORCID: https://orcid.org/0000-0003-2947-7606)
- Anna E. Steindorsdottir (ORCID: https://orcid.org/0000-0002-2386-5934)
- Þórarinn Jónmundsson (ORCID: https://orcid.org/0000-0001-9158-0087)
- Sergi Valero (ORCID: https://orcid.org/0000-0002-6599-948X)
- Elías F. Guðmundsson (ORCID: https://orcid.org/0000-0002-7661-4872)
- Elísabet A. Frick (ORCID: https://orcid.org/0000-0002-9812-361X)
- Valur Emilsson (ORCID: https://orcid.org/0000-0001-9982-0524)
- Thor Aspelund (ORCID: https://orcid.org/0000-0002-7998-5433)
- Anantharaman Shantaraman (ORCID: https://orcid.org/0000-0003-1384-941X)
- Raquel Puerta (ORCID: https://orcid.org/0000-0002-1191-5893)
- Alexander Guðjónsson (ORCID: https://orcid.org/0000-0002-3273-8478)
- Xiazi Qiu (ORCID: https://orcid.org/0000-0002-8397-2168)
- Pablo García‐González (ORCID: https://orcid.org/0000-0003-0125-5403)
- Nancy Finkel (ORCID: https://orcid.org/0000-0002-8937-4150)
Institutions
- Genomics Institute of the Novartis Research Foundation (US)
- Emory University (US)
- University of Iceland (IS)
- Instituto de Salud Carlos III (ES)
- Universitat Internacional de Catalunya (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Novartis (United States) (US)
- Fundació ACE (ES)
- National Institute on Aging (US)
- Icelandic Heart Association (IS)
Publication Details
- Journal
- Nature Aging
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s43587-024-00693-1
- Citations
- 31
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 10.12
Funders
- Agentschap Innoveren en Ondernemen
- Icelandic Centre for Research
- Innovative Medicines Initiative
- Instituto de Salud Carlos III
- National Institute on Aging