Digital Dual‐Dimensional α‐Synuclein Aggregate Decoding Sensor for Parkinson's Disease Diagnostics

Abstract α‐Synuclein (α‐syn) aggregation is a hallmark of Parkinson's disease (PD) pathology. In blood, α‐syn aggregates (α‐syn Agg) exist either freely (free‐α‐syn Agg) or bound to neuron‐derived extracellular vesicles via L1CAM (L1EV‐α‐syn Agg). However, the lack of sensitive tools to distinguish these two forms hampers PD diagnostics. Here, a dual‐channel biosensor that simultaneously detects free‐α‐syn and L1EV‐α‐syn Agg in serum using ultra‐bright optical signals is introduced. The biosensor employs specific antibody pairs on magnetic beads and aggregation‐induced emission (AIE) fluorophores to generate distinct orange‐red and yellow‐green fluorescence for each α‐syn Agg type, forming stable immunosandwich complexes. It performs robustly in both liquid‐phase and solid‐phase assays. With AI‐assisted image recognition, it enables rapid and accurate detection of α‐syn Agg based on dual‐color signatures. This strategy allows for effective differentiation of PD from healthy controls in clinical samples, achieving an AUC of 0.98 (specificity = 0.96, sensitivity = 0.90). By integrating dual dimensions of α‐syn pathology, this method offers a promising tool for precise, non‐invasive PD diagnosis, and sets the foundation for future clinical translation in neurodegenerative biomarker detection.