Alzheimer's disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
- ■ In-depth proteomics workflow for profiling paired cerebrospinal fluid (CSF) and serum proteomes.
- ■ Independent multicenter set combined with multiple methods for validation.
- ■ Development of 19 CSF- and 8 serum-protein panels for early of Alzheimer disease (AD) diagnosis.
- ■ Twenty-one CSF and 18 serum proteins dysregulated in different AD stages.
- ■ Groundwork laid for AD blood tests in clinical screening and staging.
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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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REFERENCES
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Cite this article:
Qing-Qing Tao, Xue Cai, Yan-Yan Xue, Weigang Ge, Liang Yue, Xiao-Yan Li, Rong-Rong Lin, Guo-Ping Peng, Wenhao Jiang, Sainan Li, Kun-Mu Zheng, Bin Jiang, Jian-Ping Jia, Tiannan Guo, Zhi-Ying Wu. Alzheimer's disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling[J]. The Innovation, 2024, 5(1). https://doi.org/10.1016/j.xinn.2023.100544
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Qing-Qing Tao, Xue Cai, Yan-Yan Xue, Weigang Ge, Liang Yue, Xiao-Yan Li, Rong-Rong Lin, Guo-Ping Peng, Wenhao Jiang, Sainan Li, Kun-Mu Zheng, Bin Jiang, Jian-Ping Jia, Tiannan Guo, Zhi-Ying Wu. Alzheimer's disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling[J]. The Innovation, 2024, 5(1). https://doi.org/10.1016/j.xinn.2023.100544
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Figure 1.
Overview of the study populations and schematic of the proteomic workflow
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Figure 2.
Dysregulated CSF and serum proteins and pathways in the diagnosis of early AD
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Figure 3.
Differentiation of MCI due to AD and CN subjects by machine learning of CSF proteomic features
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Figure 4.
Differentiation of MCI due to AD and CN by machine learning of serum proteomic features
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Figure 5.
Dysregulated CSF and serum proteins as potential biomarkers for AD staging
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Figure 6.
Verification of AD stage-dependent dysregulated proteins in the validation cohort
