Abstract
Background: The aim of this paper is to investigate the causality of the inverse associa- tion between cigarette smoking and Parkinson’s disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individ- uals from NeuroEPIC4PD, a prospective European population-based cohort study includ- ing 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose–response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67–1.07], 20–29 years 0.73 (95% CI 0.56–0.96) and >30 years 0.54 (95% CI 0.43–0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose–response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49–0.99) ruled out the effect of unmeasured confounding. Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking re- sponsible for the biological effect.