Differential Proteomic Response to Smoking Exposure Underlies Reduced Parkinson's Disease Risk in Women

Background The inverse association between cigarette smoking and Parkinson's disease (PD) risk, often termed the "smoker's paradox," remains one of the most reproducible observations in neuroepidemiology. Although multiple biological mechanisms have been proposed, the molecular correlates of smoking exposure in large human populations remain incompletely characterized. Methods We analyzed proteomic data from the UK Biobank Olink Explore 3072 platform to evaluate associations between cumulative smoking exposure and circulating proteins implicated in proteostasis, cellular stress responses, and neuronal biology. Sex-stratified linear regression models were performed with adjustment for age at recruitment. Results Among female participants, cumulative smoking exposure was associated with significantly higher circulating HSPA1A (HSP70) levels (p = 1.82 × 10⁻⁶), while BAG3 demonstrated a nominal positive association (p = 0.02). Independent analyses demonstrated that both smoking exposure (p = 0.0125) and circulating estradiol concentrations (p < 2 × 10⁻¹⁶) were associated with HSPA1A expression. No statistically significant smoking-by-estradiol interaction was observed (p = 0.3465). Additional associations involving BAG3 and CASP3 did not survive strict multiple-testing correction and should be considered exploratory. No significant associations were observed between smoking exposure and circulating dopa decarboxylase (DDC) levels. Conclusions Smoking exposure was associated with sex-specific differences in circulating proteomic biomarkers related to cellular stress-response and proteostasis pathways. These findings identify population-level proteomic signatures associated with cumulative smoking exposure and generate hypotheses for future mechanistic and longitudinal investigations. Because the study is observational and relies on peripheral blood biomarkers, the results should not be interpreted as evidence of causal neuroprotective mechanisms.