Multi-platform proteomic analysis of Alzheimer’s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome
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Abstract
Robust and accessible biomarkers that can capture the heterogeneity of Alzheimer’s disease and its diverse pathological processes are urgently needed. Here, we undertook an investigation of Alzheimer’s disease cerebrospinal fluid (CSF) and plasma from the same subjects ( n= 18 control , n= 18 AD) using three different proteomic platforms—SomaLogic SomaScan, Olink proximity extension assay, and tandem mass tag-based mass spectrometry—to assess which protein markers in these two biofluids may serve as reliable biomarkers of AD pathophysiology observed from unbiased brain proteomics studies. Median correlation of overlapping protein measurements across platforms in CSF ( r ~0.7) and plasma ( r ~0.6) was good, with more variability in plasma. The SomaScan technology provided the most measurements in plasma. Surprisingly, many proteins altered in AD CSF were found to be altered in the opposite direction in plasma, including important members of AD brain co-expression modules. An exception was SMOC1, a key member of the brain matrisome module associated with amyloid-β deposition in AD, which was found to be elevated in both CSF and plasma. Protein co-expression analysis on greater than 7000 protein measurements in CSF and 9500 protein measurements in plasma across all proteomic platforms revealed strong changes in modules related to autophagy, ubiquitination, and sugar metabolism in CSF, and endocytosis and the matrisome in plasma. Cross-platform and cross-biofluid proteomics represents a promising approach for AD biomarker development.
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Comparing 388 index variants with overlapping proteins on an antibody-based (Olink) platform, the study observed good correlation (R=0.69, P<2.2×10−16).
“Comparing 388 index variants with overlapping proteins on an antibody-based (Olink) platform (Amsterdam Dementia Cohort, ADC; N=502), we observed good correlation (R=0.69, P<2.2×10−16, Supp. Fig. 6, Supp. Table S5) which is consistent with protein level correlations between SOMAscan and Olink in CSF26, and support the pQTLs identified in this study”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [26]
SOMAscan-based measurements correlate well with complementary approaches.
“Nonetheless, we note that SOMAscan-based measurements correlate well with complementary approaches26,97.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [26]
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“Such proteoform complexity is very likely to be a large driver of variation across proteomic measurements within and across platforms, where a given platform is targeting a particular epitope or peptide for measurement of protein levels that could be obscured by splice variation, PTMs, or complex formation [18, 33].”
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- Authors
- Dammer, E. B., Ping, L., Duong, D. M., Modeste, E. S., Seyfried, N. T., Lah, J. J., Levey, A. I., & Johnson, E. C. B.
- Affiliations
- Emory University (US)
- Corresponding author
- Johnson, Erik C. B.
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2022-11-17
- Volume
- 14
- Issue
- 1
- Pages
- 174-174
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC9670630
- OpenAlex
- W4309511017
- Cited by
- 188
- References
- 13
- Citations by year
- 2026: 40 · 2025: 60 · 2024: 55 · 2023: 32 · 2022: 1
- FWCI
- 23.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute on Aging (K08AG068604, U54AG065187, P30AG066511)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- Alzheimer's disease, cerebrospinal fluid, plasma, biomarkers, proteostasis, matrisome, SMOC1, amyloid-beta deposition, autophagy, ubiquitination, endocytosis
- MeSH terms
- Proteostasis, Alzheimer Disease, Humans, Biomarkers, Amyloid beta-Peptides, Proteomics
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