Objective:

To define and contrast the molecular trajectories of blood biomarkers before and after the clinical onset of Parkinson's disease (PD).

Background:

PD can disrupt a wide range of physiological processes, including inflammation, digestion, hormone signaling, and cognition. While multiple groups have highlighted protein biomarkers for early PD detection, data comparing early- and late-stage disease markers, and what they signify about disease progression, are critically lacking.

Design/Methods:

We analyzed 602 confirmed PD patients and 6,026 age- and sex-matched neurologically healthy controls (NHCs) with proteomic profiling from the UK Biobank. Protein abundances were normalized to z-scores against NHCs, controlling for age and sex. Statistical analyses included Mann-Whitney U tests comparing cases (both pre- and post-diagnosis) with NHCs, forward and reverse time Cox survival analysis, and Pearson correlation against time relative to the algorithmically determined PD diagnosis date.

Results:

Levels of dopamine decarboxylase (DDC), prolactin (PRL), cholinesterase (BCHE), and Protein LEG1 homolog (LEG1) were altered only after diagnosis, likely confounded by the patients' use of levodopa and cholinesterase inhibitors. In contrast, biomarkers from protein quality control pathways (e.g., BAG3 and DPEP1) showed a strong signal before diagnosis that dimmed after clinical onset. Other plasma proteins, such as Neurofilament light chain (NEFL) and Hematopoietic prostaglandin D synthase (HPGDS), distinguished PD cases from NHCs but showed no correlation with disease duration, suggesting they track the presence of PD, not its duration.

Conclusions:

PD-associated blood biomarker signals appear seven or more years prior to the emergence of clinical signs. Candidate biomarkers exhibit diverse trajectories, which reflect distinct biological roles across the disease course. Proteomic changes due to common PD medications are substantial and can overshadow underlying pathophysiology. We conclude that successful blood-based monitoring requires contextualizing the biomarker signal against both NHC ranges and disease duration to provide reliable insights into PD progression.