Smoking and risk of amyotrophic lateral sclerosis: A pooled analysis of 5 prospective cohorts

Background: Cigarette smoking has been proposed as a risk factor for amyotrophic lateral sclerosis (ALS), but epidemiological studies supporting this hypothesis have been small and mostly retrospective. Objective: To prospectively examine the relation between smoking and ALS in 5 well-established large cohorts. Design: Five prospective cohorts with study-specific follow-up ranging from 7 to 28 years. Setting: Academic research. Patients: Participants in the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, and the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study. Main Outcome Measures: Amyotrophic lateral sclerosis deaths identified through the National Death Index. In the Nurses' Health Study and the Health Professionals Follow-up Study, confirmed nonfatal incident ALS was also included. Results: A total of 832 participants with ALS were documented among 562 804 men and 556 276 women. Smokers had a higher risk of ALS than neversmokers, withage-and sex-adjusted relative risks of 1.44 (95% confidence interval, 1.23-1.68;P<.001) for former smokers and 1.42(95% confidence interval, 1.07-1.88; P=.02) for current smokers. Although the risk of ALS was positively associated with pack-years smoked (P<.001), duration of smoking (9%increase for each 10 years of smoking, P=.006), and the number of cigarettes smoked per day (10% increase for each increment of 10 cigarettes smoked per day, P<.001), these associations did not persist when never smokers were excluded. However, among ever smokers, the risk of ALS increased as age at smoking initiation decreased (P=.03). Conclusions: Results of this large longitudinal study support the hypothesis that cigarette smoking increases the risk of ALS. The potential importance of age at smoking initiation and the lack of a dose response deserve further investigation.