Blood analysis of DNA repair genes ERCC6, PRIMPOL, NEIL2, and NTHL1 successfully distinguished individuals in prodromal Parkinson's from healthy controls with peak accuracy in later pre-motor stages. The integrated stress response pathway showed even stronger predictive power, with 74% of genes displaying non-linear expression patterns suggesting transient adaptive mechanisms. This represents a potential paradigm shift in Parkinson's biomarker research, as these molecular signatures proved most diagnostic during the prodromal phase rather than after motor symptoms emerge. The finding aligns with emerging evidence that neurodegeneration triggers early cellular repair responses before these systems become overwhelmed. High initial gene expression variability that converges over time suggests the brain's attempt to compensate for accumulating damage. The temporal specificity is particularly intriguing—DNA repair dysfunction appears most detectable when intervention might be most beneficial. However, validation in larger cohorts is essential, as the Parkinson's Progression Markers Initiative represents a relatively homogeneous population. If confirmed, this could enable screening programs targeting at-risk individuals years before clinical diagnosis, when neuroprotective strategies might preserve more neural function.