A low-cost hierarchical nanowire-based electrode was developed for pain-free detection of alpha-synuclein, a biomarker for Parkinson's disease (PD). The biosensor uses hierarchical polyglutamic acid/ZnO nanowires decorated with gold nanoparticles (Au NPs) arranged as nanostars (NSs). ZnO NSs were synthesized via chemical bath deposition and decorated with Au NPs. Electro-polymerized glutamic acid was then grown and functionalized with anti-alpha-synuclein. The synergistic enhancement of electrode sensitivity was observed when Au NPs were embedded into ZnO NSs. The biosensor was evaluated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) with the Fe(II)(CN)₆⁴⁻/Fe(III)(CN)₆³⁻ probe. The charge transfer resistance after alpha-synuclein recognition was found to be linear, with a concentration range of 0.5 to 10 pg·mL⁻¹, a limit of detection of 0.08 pg·mL⁻¹, and good reproducibility (5% variation) and stability (90%). The biosensor reliably discriminated between healthy plasma and PD plasma. The results suggest that the biosensor provides a rapid, quantitative, and high-sensitivity detection of alpha-synuclein in plasma, making it a feasible tool for early and non-invasive identification of PD. The biosensor was tested with clinical samples from PD and healthy control (HC) patients, showing good discrimination between the two. The matrix effects related to plasma were found to be marginal, and the biosensor was suitable for alpha-synuclein detection in real plasma. The biosensor is non-invasive, rapid, and reproducible, making it a promising tool for PD diagnosis.A low-cost hierarchical nanowire-based electrode was developed for pain-free detection of alpha-synuclein, a biomarker for Parkinson's disease (PD). The biosensor uses hierarchical polyglutamic acid/ZnO nanowires decorated with gold nanoparticles (Au NPs) arranged as nanostars (NSs). ZnO NSs were synthesized via chemical bath deposition and decorated with Au NPs. Electro-polymerized glutamic acid was then grown and functionalized with anti-alpha-synuclein. The synergistic enhancement of electrode sensitivity was observed when Au NPs were embedded into ZnO NSs. The biosensor was evaluated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) with the Fe(II)(CN)₆⁴⁻/Fe(III)(CN)₆³⁻ probe. The charge transfer resistance after alpha-synuclein recognition was found to be linear, with a concentration range of 0.5 to 10 pg·mL⁻¹, a limit of detection of 0.08 pg·mL⁻¹, and good reproducibility (5% variation) and stability (90%). The biosensor reliably discriminated between healthy plasma and PD plasma. The results suggest that the biosensor provides a rapid, quantitative, and high-sensitivity detection of alpha-synuclein in plasma, making it a feasible tool for early and non-invasive identification of PD. The biosensor was tested with clinical samples from PD and healthy control (HC) patients, showing good discrimination between the two. The matrix effects related to plasma were found to be marginal, and the biosensor was suitable for alpha-synuclein detection in real plasma. The biosensor is non-invasive, rapid, and reproducible, making it a promising tool for PD diagnosis.