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A High Throughput, Multiplexed and Targeted Proteomic CSF Assay to Quantify Neurodegenerative Biomarkers and Apolipoprotein E Isoforms Status
Published on: October 20, 2016
Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer's
Junyoung Park1,2, Yann Le Guen1, Andrés Peña-Tauber2
1Quantitative Sciences Unit, Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA 94304, USA.
Medrxiv : the Preprint Server for Health Sciences
|July 17, 2026
Summary
This study identifies 30 plasma proteins that change over time in Alzheimer's disease (AD), distinguishing progression markers from diagnostic states. These proteins offer new avenues for AD biomarker development and therapeutic strategies.
Area of Science:
- Neuroscience
- Proteomics
- Biomarker Discovery
Background:
- Most Alzheimer's disease (AD) plasma proteomic studies use cross-sectional designs, failing to differentiate between proteins indicating disease state and those reflecting disease progression.
- Understanding longitudinal changes in plasma proteins is crucial for identifying reliable AD biomarkers and therapeutic targets.
Purpose of the Study:
- To differentiate between plasma protein changes associated with the diagnostic state of Alzheimer's disease (AD) and those linked to disease progression.
- To identify and prioritize a signature of plasma proteins indicative of AD progression using a longitudinal, multi-domain approach.
Main Methods:
- Utilized longitudinal SomaScan proteomic profiling from the Global Neurodegeneration Proteomics Consortium (13,449 participants, 17,269 samples).
- Employed linear mixed-effects models to identify proteins with concordant baseline and AD-by-time effects, defining a 30-protein signature.
- Prioritized proteins based on five evidence domains: clinical progression, AD biomarker alignment, cerebrospinal fluid concordance, prospective replication (UK Biobank), and genetic support (Mendelian randomization, rare-variant burden).
Main Results:
- A 30-protein signature was defined, distinguishing baseline AD differences from AD-specific changes over time.
- Thirteen proteins were supported by two or more evidence domains, with six proteins supported by three.
- Proteins in the signature aligned more strongly with tau and neuronal-injury markers than with amyloid-beta (Aβ) 42/40.
- EDA2R, HPGDS, ITGAV, and CLEC3B showed convergence across clinical, biomarker, and prospective evidence.
- ANTXR1 demonstrated direction-concordant plasma pQTL Mendelian randomization and rare-variant burden signals.
Conclusions:
- This longitudinal, multi-domain approach successfully distinguishes diagnostic-state markers from progression-linked changes in Alzheimer's disease (AD).
- The identified protein signature prioritizes candidates for validation as AD progression biomarkers.
- These findings support further investigation of prioritized proteins for mechanistic understanding and therapeutic development in AD.
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