Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease
Open accessAbstract
To date, the development of disease-modifying therapies for Alzheimer’s disease (AD) has largely focused on the removal of amyloid beta Aβ fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q < 0.05). We identified, and replicated, altered levels of ten CSF proteins in Aβ+ individuals, including CHIT1, SMOC2, MMP-10, LDLR, CD200, EIF4EBP1, ALCAM, RGMB, tPA and STAMBP (− 0.14 < d < 1.16; q < 0.05). We also identified and replicated alterations of six plasma proteins in Aβ+ individuals OSM, MMP-9, HAGH, CD200, AXIN1, and uPA (− 0.77 < d < 1.28; q < 0.05). Multiple analytes associated with cognitive performance and cortical thickness ( q < 0.05). Plasma biomarkers could distinguish AD dementia (AUC = 0.94, 95% CI = 0.87–0.98) and prodromal AD (AUC = 0.78, 95% CI = 0.68–0.87) from CN. These findings reemphasize the contributions of immune markers, phospholipids, angiogenic proteins and other biomarkers downstream of, and potentially orthogonal to, Aβ- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration.
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Most proteins were measured using validated, highly sensitive and specific PEA developed by Olink Proteomics.
“Most proteins were measured using validated, highly sensitive and specific PEA developed by Olink Proteomics (Uppsala, Sweden) as described before (Whelan et al, 2019).”
From The genetic regulation of protein expression in cerebrospinal fluid (2023) · cites this paper as Whelan et al, 2019
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Cerebrospinal fluid proteomic study of two bipolar disorder cohorts
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AI-assisted multi-OMICS analysis reveals new markers for the prediction of AD
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- Authors
- Whelan, C. D., Mattsson, N., Nagle, M. W., Vijayaraghavan, S., Hyde, C., Janelidze, S., Stomrud, E., Lee, J., Fitz, L., Samad, T. A., Ramaswamy, G., Margolin, R. A., Malarstig, A., & Hansson, O.
- Affiliations
- Biogen (United States) (US)
- Lund University (SE)
- Pfizer (United States) (US)
- Karolinska Institutet (SE)
- Sanofi (United States) (US)
- Corresponding author
- Hansson, Oskar
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2019-11-06
- Volume
- 7
- Issue
- 1
- Pages
- 169-169
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC6836495
- OpenAlex
- W2985460727
- Cited by
- 262
- References
- 62
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 50 · 2023: 42 · 2022: 46 · 2021: 39 · 2020: 18
- FWCI
- 20.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- H2020 European Research Council (__)
- Swedish Research Council (___)
- Knut och Alice Wallenbergs Stiftelse (___)
- Marianne and Marcus Wallenberg Foundation (____)
- MultiPark (___)
- Swedish Alzheimer Foundation (__)
- Pfizer (Digital Data Innovation)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, early detection, biomarkers, cerebrospinal fluid protein, plasma proteins, amyloid-beta, mild cognitive impairment, prodromal Alzheimer's disease, CHIT1, SMOC2, MMP-10, CD200, MMP-9, uPA, tissue plasminogen activator, OSM, AXIN1, 4E-BP1
- MeSH terms
- Aged, Alzheimer Disease, Female, Humans, Immunoassay, Male, Middle Aged, Cohort Studies, Amyloid beta-Peptides, Proteomics
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