Immunotherapy in Early Parkinson's Disease: A Biomarker-Driven Trial Framework for Secondary Prevention.

Parkinson's disease (PD) is characterized by α-synuclein aggregation and progressive dopaminergic neuron loss that begins years before motor symptoms appear. This prolonged premotor phase creates an opportunity for intervention before extensive neurodegeneration. Biomarkers, including α-synuclein seed amplification assays, standardized peripheral tissue biopsies (e.g., skin biopsies for phosphorylated α-syn), neuroimaging, fluid biomarkers, genetics, and digital measures, now detect prodromal PD biology in at-risk individuals and enable secondary-prevention-style trials. Immunotherapy targeting misfolded α-synuclein is a leading disease-modification strategy. Passive approaches (monoclonal antibodies) and active vaccines have shown target engagement in preclinical models and early trials. Phase 1/2 α-synuclein antibody trials have shown mainly mild-to-moderate infusion reactions and no reproducible CNS inflammatory toxicity. Although primary efficacy endpoints have not yet been achieved overall, prasinezumab has indicated exploratory slowing in faster progressors and digital measures. MEDI1341 has demonstrated Phase 1 target engagement with acceptable safety, and Lu AF82422 has shown Phase 1 target engagement, along with promising subgroup trends in MSA, and scheduled Phase 3. Meanwhile, cinpanemab was negative. However, signals of slowed progression in subgroups underscore the importance of treating earlier and selecting patients with biomarker-confirmed pathology. This review synthesizes evidence supporting early, biomarker-anchored intervention and the status of α-synuclein immunotherapies. Treating PD at the prodromal stage aims to preserve vulnerable neurons and alter the disease course; continued advances in biomarkers and trial design are essential to realize this potential. We emphasize biomarkers that verify α-synuclein pathology during the asymptomatic phase and argue for a secondary-prevention model that treats the underlying biology before symptoms to maximize disease-modifying potential. We also propose a practical, biomarker-guided trial blueprint for secondary prevention, with explicit screening funnels and endpoint hierarchies.