In this prospective study, we observed that cigarette smoking was associated with a significantly higher risk of ALS. Significant trends in the risk of ALS were observed with the years smoked and the number of cigarette smoked per day, but these trends were largely driven by the low ALS risk among never smokers. Among individuals who ever smoked, risk of ALS increased with decreasing age at smoking initiation, but not with duration or intensity of smoking.
The strengths of the current study include the prospective design and the large number of participants with ALS. These cohorts are more likely to be representative of the whole spectrum of ALS patients, avoiding selection that is likely when patients are recruited in ALS tertiary care centers.36
One limitation is the use of ALS mortality in the CPS-II Nutrition Cohort, MEC and AARP-DH studies as a proxy for ALS incidence. We assume, however, that mortality is a reasonable surrogate for incidence, because median survival of ALS after diagnosis (1.5 – 3 years) is relatively short.2, 37–39
Death certificates have been estimated to accurately identify 70–90% of ALS or motor neuron diseases related deaths,40–43
thus bias is unlikely unless the underreporting is strongly related to smoking. In addition, use of mortality could result in inclusion of prevalent ALS at baseline, but sensitivity analyses that excluded the first 4 years of follow-up in each cohort showed very similar results. Although the study population was not chosen to be representative of the US population, the ALS mortality rates among participants in these five cohorts are comparable to those of the US population of similar age and sex.33, 34
Baseline cigarette smoking information was used in the analysis as the questionnaire for the period of this analysis in the MEC and the AARP-DH studies was administered only once, therefore changes in cigarette smoking during the follow-up were not captured. While measurement error in BMI, education or physical activity may result in residual confounding, it is unlikely to explain the strong results reported.
Our results are consistent with recent epidemiologic evidence that links cigarette smoking with an increased risk of ALS. In a population-based case-control study in Washington state, investigators reported an odds ratio (OR) of 2 (95% CI: 1.3–3.2) for the broad smoking category of ever-smokers compared to never smokers.6
They also found a significant increase in risk of ALS among those with more pack-years of smoking and longer duration of smoking. In a case-control study in New England, cigarette smoking was associated with a significant 70% increase in ALS risk.5
This study, however, did not find a dose-response across pack-years or years smoked. A case-control study in the Netherlands including 364 cases found an OR of 1.7 (95% CI: 1.1–2.6) for current smokers and 1.6 (95% CI: 1.0–2.5) for former smokers compared to never smokers.7
Among smokers, no dose-response for pack-years was observed. More recently, Weisskopf et al reported that mortality from ALS in the CPS-II mortality cohort (the parent cohort for CPS-II Nutrition Cohort) was 70% higher among female smokers, but was not elevated among male smokers (RR=0.7 [95% CI:0.5–1.0]),14
indicating a possible gender difference in the determinants of ALS. We did not find significant gender differences in the association between cigarette smoking and ALS. In a recent analysis of the multi-centered EPIC cohort, current smokers had about a two-fold increase in ALS rates compared to never-smokers (RR=1.89; 95% CI: [1.14–3.14]) while former smokers had a 50% increased rate (RR=1.48; 95% CI: [0.94–2.32]). The authors also reported a dose-response across number of years spent smoking but not pack-years smoked.16
Several possible mechanisms by which cigarette smoke might influence the risk of ALS have been suggested, including direct neuronal damage from nitric oxide or other components of cigarette smoke,44
such as residues of pesticides used in tobacco cultivation,45
or oxidative stress. Chemicals that are present in cigarette smoke generate free radicals and products of lipid peroxydation,46
and smokers have a higher turnover of the major antioxidant vitamin C.47
Exposure to formaldehyde, a by-product of the combustion process of tobacco smoking, was recently reported to be associated with an increased risk of ALS.48
Inhibition of vascular endothelial growth factor (VEGF) has also been postulated as a possible explanation for smoke-related effects on neurons.49
On the other hand, the observation that among smokers ALS risk is affected by age at smoking initiation, but not by duration or intensity of smoking, seems hard to reconcile with a simple toxic effect of tobacco components or additives. Because of the large sample size, it is unlikely that a strong dose-response relation between pack-years of smoking and ALS risk would have been missed in our study. Possible explanations for the lack of a biological gradient include: i) smoking is only relevant at a young age, perhaps during adolescence when the body is still growing and motor neurons are under additional stress; ii) smoking may act in genetically or otherwise susceptible individuals by triggering an autoimmune or otherwise self-perpetuating neurodegenerative process that then runs its course independently of smoking behavior; iii) long term, heavy smoking survivors are a selected group, with low genetic susceptibility to ALS; and iv) one or more of the several hundred chemicals contained in tobacco smoke is neuroprotective and with chronic exposure compensate for the adverse effects of other chemicals. The latter hypothesis may seem far-fetched, but it is indirectly corroborated by the very low risk of Parkinson disease among smokers.50, 51
Finally, as in all observational studies, confounding by unmeasured factors could explain the findings presented; an association with smoking could reflect a true association with another behavior related to being a smoker.
In summary, in this large longitudinal investigation based on five cohorts of US men and women, we observed that the risk of ALS was higher for cigarette smokers compared with never smokers. Among smokers, the risk of ALS increased with decreasing age at smoking initiation, but was unrelated to smoking duration or intensity. A better understanding of the relation between smoking and ALS may further the discovery of other risk factors and help elucidate the nature of the disease.