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Cited by 55Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAdvanced Proteomics Techniques and Applications

Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

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Tao, Qing-Qing, Cai, Xue, Xue, Yan-Yan, Ge, Weigang, Yue, Liang, Li, Xiao-Yan, Lin, Rong-Rong, Peng, Guo-Ping +7 more·2024·The Innovation
DOI 10.1016/j.xinn.2023.100544PMC PMC10794110
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Abstract

Amyloid-β, tau pathology, and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease (AD). However, these proteins represent only a fraction of the complex biological processes underlying AD, and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers. More AD-specific early diagnostic and disease staging biomarkers are needed. In this study, we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid (CSF) and serum samples in a discovery cohort comprising 98 participants. Candidate biomarkers were validated by parallel reaction monitoring-based targeted proteomic assays in an independent multicenter cohort comprising 288 participants. We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort, identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers, respectively. In the validation cohort, 58 and 21 CSF proteins, as well as 12 and 18 serum proteins, were verified as early diagnostic and staging biomarkers, respectively. Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment (MCI) due to AD from normal cognition with areas under the curve of 0.984 and 0.881, respectively. The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases. Moreover, we identified 21 CSF and 18 serum stage-associated proteins reflecting AD stages. Our findings provide a foundation for developing blood-based tests for AD screening and staging in clinical practice.

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  • Pcdh-γC5 expression level increased significantly in the cerebrospinal fluid of Alzheimer's disease patients.

    “The expression level of Pcdh-γC5 increased significantly in the CSF of AD patients, highlighting Pcdh-γC5 as a potential early-stage biomarker of AD (Tao et al., 2024).”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Tao et al., 2024

    The Results section on independent validation identifies PCDHGC5 as part of a 19-protein CSF panel for early diagnosis of MCI due to AD, supporting its potential as an early-stage biomarker. Our copy does not state that PCDHGC5 itself increased significantly: the passage explicitly reports upregulation for four other proteins, not PCDHGC5. Page numbers are unavailable in the indexed passages. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Pcdh-γC5 has been implicated in Alzheimer's disease pathogenesis.

    “Pcdh-γC5 has been implicated in AD pathogenesis (Nativio et al., 2018;Tao et al., 2024), prompting us to examine its expression in 5×FAD mice”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Tao et al., 2024

    The Results section on validation in MCI due to AD includes PCDHGC5 among differentially expressed proteins and identifies it as related to immune function. That supports an association with AD, but the paper does not establish a role for PCDHGC5 in AD pathogenesis. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Pcdh-γC5 correlates with the level of both Aβ42 and phosphorylated tau (p-tau181) in cerebrospinal fluid of Alzheimer's disease patients.

    “Pcdh-γC5, a member of Pcdh-γs, was revealed to correlate with the level of both Aβ 42 and phosphorylated tau (p-tau 181 ), the two most prominent hallmarks of AD.”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Tao et al., 2024

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Authors
Tao, Q.-Q., Cai, X., Xue, Y.-Y., Ge, W., Yue, L., Li, X.-Y., Lin, R.-R., Peng, G.-P., Jiang, W., Li, S., Zheng, K.-M., Jiang, B., Jia, J.-P., Guo, T., & Wu, Z.-Y.
Affiliations
  • Second Affiliated Hospital of Zhejiang University (CN)
  • Westlake University (CN)
  • Xiamen University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Guo, Tiannan
  • Wu, Zhi-Ying
ORCID
Venue
The Innovation
Publisher
Elsevier BV
Published
2024-01
Volume
5
Issue
1
Pages
100544
ISSN
2666-6758 (ISSN-L)
DOI
10.1016/j.xinn.2023.100544
PMC
PMC10794110
OpenAlex
W4390510168
Cited by
55
References
11
Citations by year
2026: 12 · 2025: 30 · 2024: 13
FWCI
14.87
Type
journal article
Language
en
Open access
Licence
Locations
  • The Innovation (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81970998, 2021ZD0201803, 2021ZD0201103)
  • Key Research and Development Program of Zhejiang Province (2019C03039)
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
Alzheimer's disease, early diagnosis, disease staging, cerebrospinal fluid biomarkers, serum biomarkers, proteomic profiling, mild cognitive impairment, amyloid-beta, tau pathology, neurodegeneration, blood-based screening, biomarker panel, machine learning classification, neurodegenerative disease comorbidity

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