To systematically review studies assessing the association of plasma α-synuclein with Parkinson’s disease (PD), focusing on non-motor symptoms and exploring differences in α-synuclein types, symptom profiles, and assay methods.

α-synuclein plays a central role in the development of PD. The relatively invasive procedure for collecting CSF has led to investigations of serum or plasma as alternatives. Emerging evidence suggests it may be linked to non-motor symptoms such as cognitive impairment (CI), REM Sleep Behavior Disorder (RBD), depression, fatigue, olfactory loss, and others, yet findings remain inconsistent. 

A systematic search was conducted on PubMed, Scopus, and Embase to identify studies published up to 27/6/2025 that assess the relationship between the level of several α-synuclein variants, and the occurrence of non-motor symptoms. After screening 539 de-duplicated studies, 22 were included. Publication bias was assessed via the Newcastle–Ottawa Scale (NOS). Data analysis was performed using Review Manager V5.4. We calculated the Standardized mean differences (SMD) with 95% confidence intervals (CI) using a random-effects model, and a sensitivity analysis was performed to assess heterogeneity.

We identified twenty-two studies, involving a total of 2131 PD patients. A significant decrease in p-α-synuclein was found in PD patients with RBD and olfactory loss Compared to patients without these symptoms , while an increase in total α- synuclein was observed in patients with CI. We support these results by conducting a meta-anlaysis, which found a significant SMD (SMD=0.79,95%CI:0.18-1.40,p=0.01, I²=94%) between PDD and PD-NC in ten studies, and(SMD=0.57,95%CI:0.12-1.02,p=0.01, I²=87%) between PD-MCI and PD-NC in nine studies. Heterogeneity was mainly due to one outlier study; its exclusion reduced I² while maintaining significant results.

In conclusion, plasma α-synuclein may serve as a potential non-invasive biomarker for non-motor symptoms in PD patients, suggesting that α-synuclein could be a promising marker to distinguish between patients who develop non-motor symptoms and those who do not.