The decades-old observation that smoking is linked to a lower risk for Parkinson's disease (PD) has resurfaced in a large national cohort study — this time with closer examination of how smoking patterns may influence the association.

Investigators found that continued smoking was associated with a lower risk for PD among adults who smoked in midlife, whereas smoking cessation was associated with reduced all-cause mortality.

Results of the nationwide cohort of more than 410,000 adults showed that current smokers had the lowest incidence of PD, while those who quit — whether recently or long ago — had roughly a 60% higher risk after accounting for death as a competing event. In contrast, individuals who quit but later relapsed had a PD risk comparable to those who had never quit smoking.

“The severe health risks of smoking cannot be overlooked, as it remains a leading cause of preventable death and contributes to heart disease, cancer, and chronic lung disorders,” study investigator Jun-Hyuk Lee, MD, PhD, of Eulji University School of Medicine in Seoul, South Korea, said in a release. 

“While our study found smokers who quit showed a higher risk of Parkinson’s disease than those who were currently smoking, it also found they had a lower risk of death. The health benefits of quitting smoking remain substantial and clear,” Lee added. 

In the release it was also noted that the link between smoking and lower PD risk is an association and should not be interpreted as evidence that smoking prevents the disease.

Led by Sung-Ho Ahn, MD, PhD, Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, the study was published online on February 25 in Neurology.

Parsing a Paradox

Epidemiologic studies have consistently shown an inverse association between cigarette smoking and PD risk, but the reasons for this remain biologically and clinically unclear. 

Factors such as smokers’ higher rates of premature death from cardiovascular disease, cancer, and respiratory illness, which may prevent PD from developing, add complexity. 

Many studies also assessed smoking status at a single time point, which limits insight into changes such as quitting or relapse. 

To examine the association between changes in smoking status and the risks of PD and all-cause mortality, the investigators conducted a retrospective cohort study using data from the Korean National Health Screening Program (NHSP). 

A total of 410,489 adults (mean age, 51.7 years; men, 93.5%) who were current smokers at baseline and completed three consecutive health examinations over approximately 4 years were included in the analysis.

Participants were categorized into four smoking trajectory groups: persistent smokers who never quit (n = 267,179); relapsed smokers who quit and later resumed smoking (n = 30,581); recent quitters who quit later in the study period (n = 54,243); and sustained quitters who quit early and remained abstinent (n = 58,486).

Persistent smokers had the highest lifetime tobacco exposure (median 20 pack-years) and alcohol use (75.1%), while relapsed smokers had slightly higher waist circumference (83.6 cm) and the largest proportion with low income (13.3%). 

Recent quitters were intermediate in age (53.0 years) and BMI (23.9), and sustained quitters were older (53.6 years), with the highest proportions of regular exercisers (29.7%) and hypertension (28.6%). 

Other metabolic parameters, including fasting glucose, AST, ALT, and total cholesterol, were similar across groups.

Opposing Risk Patterns

The investigators used diagnostic codes and a national registration system to identify PD. Fine-Gray competing risk regression models were used to estimate subdistribution hazard ratios (sHRs) and 95% confidence intervals, with adjustment for sex, BMI, income level, smoking pack-years, alcohol use, physical activity, hypertension, diabetes, and dyslipidemia.

Participants were followed for a median of 9.1 years; 1794 participants (0.44%) developed PD and 31,203 participants (7.6%) died.

PD occurred in 0.33% of persistent smokers, 0.41% of relapsed smokers, 0.67% of recent quitters, and 0.71% of sustained quitters.

Compared with persistent smokers, recent quitters had a significantly higher risk for PD (sHR 1.60; 95% CI, 1.41-1.82; P < .001), as did sustained quitters (sHR 1.61; 95% CI, 1.42-1.81; P < .001). Relapsed smokers did not differ significantly from persistent smokers (sHR 1.05; 95% CI, 0.87-1.28; P = .603).

Mortality showed the opposite trend: Death occurred in 7.24% of persistent smokers, 8.09% of relapsed smokers, 8.76% of recent quitters, and 7.91% of sustained quitters.

Sustained quitters had a 17% lower risk for death compared with persistent smokers (sHR 0.83; 95% CI, 0.80-0.86; P < .001). Recent quitters experienced a modest 3% lower risk (sHR 0.97; 95% CI, 0.94-1.00; P = .038), while relapsed smokers did not differ significantly from persistent smokers.

“The observed pattern of PD risk was suggested to be primarily associated with current smoking status rather than cumulative smoking exposure,” the investigators noted, emphasizing that “mortality was lowest in sustained quitters.”

These findings show that current smoking mainly influences PD risk, while quitting and staying smoke-free reduced the risk for death. This highlights the complex link between smoking, disease, and survival.

Study limitations included the reliance on self-reported smoking data, which may have led to inaccuracies in participants’ responses. Additionally, the cohort was predominantly Korean men, which may limit the generalizability of the findings to women or other populations.

'A Valuable Piece to the Puzzle'

In an accompanying editorial, Daniele Urso, MD, MPH, and Giancarlo Logroscino, MD, PhD, of the Center for Neurodegenerative Diseases and the Aging Brain, University of Bari Aldo Moro, in Bari, Italy, described the inverse association between smoking and PD as “among the most consistent and long-standing findings in neuroepidemiology,” while emphasizing that it remains unclear whether this reflects a causal relationship.

Urso and Logroscino noted that the underlying biological mechanisms remain uncertain and warrant further study. 

“Components of tobacco smoke other than nicotine, such as monoamine oxidase inhibitors, carbon monoxide at low doses, or microbiome-modulating compounds, might underlie the inverse association,” they wrote.

Of note, they cautioned against misinterpretation. “Any apparent protective signal for PD is far outweighed by the well-established mortality of smoking.” This was reinforced by the study’s observation that sustained quitters had lower all-cause mortality than persistent smokers.

Acknowledging the study’s caveats, Urso and Logroscino said that it advances the understanding of the complex relationship between smoking and PD. 

“The study by Ahn et al. contributes a valuable piece to the puzzle and illustrates how dynamically modeling exposure over time can offer a more informative perspective.” 

It provides a more nuanced view of how current smoking vs sustained cessation affects both PD risk and survival.

Ahn reported no relevant financial disclosures. Urso reported receiving honoraria for educational activities from Zambon UK Ltd. and AbbVie. Logroscino reported receiving support for attending meetings and/or travel from Roche, Eisai, Lilly, Biogen, and Piam Farmaceutici SpA, and honoraria for lectures from Roche, Eisai, and Lilly.