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Cited by 273Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease

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Whelan, Christopher D., Mattsson, Niklas, Nagle, Michael W., Vijayaraghavan, Swetha, Hyde, Craig, Janelidze, Shorena, Stomrud, Erik, Lee, Julie, Fitz, Lori, Samad, Tarek A., Ramaswamy, Gayathri, Margolin, Richard A., Malarstig, Anders, Hansson, Oskar·2019·Acta Neuropathologica Communications
DOI 10.1186/s40478-019-0795-2PMC PMC6836495
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Abstract

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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Crossref · 10.1186/s40478-019-0795-2

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Fig. 1 Proteins showing evidence of differential regulation in two or more Aβ+ groups, in a cerebrospinal fluid (CSF) and b plasma. Dashed line represents the average protein concentration of the Aβ- cognitively normal group (i.e. study controls). Aβ- groups are coloured in blue; Aβ+ groups are coloured in red. Ctrl-ABneg = Aβ- controls; MCI-ABneg = Aβ- MCI patients; Ctrl-ABpos = Aβ+ cognitively normal individuals, MCI- ABpos = Aβ+ MCI patients; AD = Dementia due to Alzheimer’s disease; q = false discovery rate adjusted p-value. Image generated using the ggplot package in R
Fig. 1 Proteins showing evidence of differential regulation in two or more Aβ+ groups, in a cerebrospinal fluid (CSF) and b plasma. Dashed line represents the average protein concentration of the Aβ- cognitively normal group (i.e. study controls). Aβ- groups are coloured in blue; Aβ+ groups are coloured in red. Ctrl-ABneg = Aβ- controls; MCI-ABneg = Aβ- MCI patients; Ctrl-ABpos = Aβ+ cognitively normal individuals, MCI- ABpos = Aβ+ MCI patients; AD = Dementia due to Alzheimer’s disease; q = false discovery rate adjusted p-value. Image generated using the ggplot package in RCC BY · PubMed Central
Fig. 2 Volcano plots illustrating the log2-transformed fold change and -log10-transformed p-value (uncorrected) for all proteins assessed in a cerebrospinal fluid and b plasma. Proteins showing evidence of differential regulation after adjustment for false discovery rate (FDR) are denoted in blue. Proteins showing evidence of differential regulation in two or more patient groups, and/or showing replicated evidence of differential regulation in the Memory Lund replication sample, are noted in green text
Fig. 2 Volcano plots illustrating the log2-transformed fold change and -log10-transformed p-value (uncorrected) for all proteins assessed in a cerebrospinal fluid and b plasma. Proteins showing evidence of differential regulation after adjustment for false discovery rate (FDR) are denoted in blue. Proteins showing evidence of differential regulation in two or more patient groups, and/or showing replicated evidence of differential regulation in the Memory Lund replication sample, are noted in green textCC BY · PubMed Central
Fig. 3 Between- and within-tissue correlation matrix, representing the strength of correlation (Pearson’s r) between proteins in plasma and cerebrospinal fluid (CSF). Positive correlations are illustrated in blue; negative correlations are illustrated in red. To reduce the dimensionality of the correlation matrix, only those proteins that were above the limit of detection, yielding Pearson’s r values equal to or greater than 0.7, were included. Image generated using the ggplot package in R
Fig. 3 Between- and within-tissue correlation matrix, representing the strength of correlation (Pearson’s r) between proteins in plasma and cerebrospinal fluid (CSF). Positive correlations are illustrated in blue; negative correlations are illustrated in red. To reduce the dimensionality of the correlation matrix, only those proteins that were above the limit of detection, yielding Pearson’s r values equal to or greater than 0.7, were included. Image generated using the ggplot package in RCC BY · PubMed Central

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  1. Alzheimer's Association, 2017. 2017 Alzheimer's disease facts and figures. Alzheimer’s & Dementia. Elsevier; 2017; 13(4): 325-373

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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
Publisher
Springer Science and Business Media LLC
Published
2019-11-06
Volume
7
Issue
1
Pages
169-169
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-019-0795-2
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
Licence
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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