Amyotrophic lateral sclerosis (ALS) rates among US men and women from the Nurses' Health Study, Health Professionals Follow-up Study, Cancer Prevention Study II Nutrition Cohort, Multiethnic Cohort, and National Institutes of Health–AARP (formerly known as the American Association of Retired Persons) Diet and Health Study.
Study-specific and pooled multivariable relative risk and 95% confidence interval of amyotrophic lateral sclerosis (ALS). The black squares and horizontal lines correspond to the study-specific multivariable relative risk and 95% confidence interval, respectively. The area of the black squares reflects the study weight (inverse of the variance). The diamonds represent the pooled multivariable relative risk and 95% confidence interval. The solid vertical lines indicate a relative risk of 1.0. A, No statistical heterogeneity was found among the risk estimates across individual studies (P = .43 for heterogeneity). Pooled relative risk, 1.10; 95% confidence interval, 1.05-1.16; P < .001. B, No statistical heterogeneity was found among the risk estimates across individual studies (P = .18 for heterogeneity). Pooled relative risk, 1.09; 95% confidence interval, 1.03-1.16; P = .006. NHS indicates Nurses' Health Study; HPFS, Health Professionals Follow-up Study; CPS-II, Cancer Prevention Study II Nutrition Cohort; MEC, Multiethnic Cohort; and NIH-AARP, National Institutes of Health–AARP (formerly known as the American Association of Retired Persons) Diet and Health Study.
Pooled multivariable relative risk and 95% confidence interval of amyotrophic lateral sclerosis for age at smoking initiation. No statistical heterogeneity was found across individual studies (P > .50 for heterogeneity). Relative risks and 95% confidence intervals were 1.61 (1.08-2.39) for smoking initiation before age 16 years, 1.35 (1.05-1.73) for 16 to younger than 20 years, 1.39 (1.06-1.80) for 20 to younger than 30 years, and 0.87 (0.54-1.39) for 30 years or older. Age- and sex-adjusted P = .03 for trend across ever smokers; multivariable adjusted P = .05. Excludes the National Institutes of Health–AARP (formerly known as the American Association of Retired Persons) Diet and Health Study, as data were unavailable. The dashed line crosses the x-axis at relative risk equals one.
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Wang H, O’Reilly ÉJ, Weisskopf MG, et al. Smoking and Risk of Amyotrophic Lateral Sclerosis: A Pooled Analysis of 5 Prospective Cohorts. Arch Neurol. 2011;68(2):207–213. doi:10.1001/archneurol.2010.367
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.
To prospectively examine the relation between smoking and ALS in 5 well-established large cohorts.
Five prospective cohorts with study-specific follow-up ranging from 7 to 28 years.
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.
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 never smokers, with age- 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).
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.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons affecting more than 5500 newly diagnosed patients every year in the United States.1 The consequence of ALS is a dramatic rapid deterioration of motor function.2 There is no cure for ALS, and the few available treatments have limited efficacy.1 About 90% of ALS cases are sporadic and of unknown, possibly environmental, origin.3 Cigarette smoking might contribute to the risk of ALS by a direct neurotoxic effect on motor neurons or by an increase in oxidative stress. Although the author of a 2009 review suggests that smoking can be considered an established risk factor for ALS, there have been few investigations, and results have been conflicting.4 A positive association between smoking and ALS has been reported in some case-control studies5-7 but not all of them.8-13 These discrepancies may in part be explained by small sample sizes and possible survival, selection, and recall bias.8-13 However, results of previous longitudinal studies14,15 have also been conflicting. In the Cancer Prevention Study II (CPS-II), an analysis that included 621 ALS deaths found that cigarette smoking was associated with increased ALS mortality in women but not in men.14 The lack of association between smoking and ALS in men was confirmed among a cohort of male construction workers in Sweden, 160 of whom died of ALS.15 However, in a 2009 multicenter prospective study16 in Europe that included 118 participants with ALS, current smokers had 2-fold increased rates of ALS compared with never smokers, with no significant differences by sex.
To better understand cigarette smoking relative to the risk of ALS, we conducted an analysis using 5 large ongoing cohort studies. In this sample, we documented 832 participants with ALS.
The study population comprised participants in the following: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), the CPS-II Nutrition Cohort, the Multiethnic Cohort (MEC), and the National Institutes of Health–AARP (formerly known as the American Association of Retired Persons) Diet and Health Study (NIH-AARP).
The NHS cohort was established in 1976 when 121 701 female registered nurses from 11 US states, aged 30 to 55 years, responded to a mailed questionnaire about disease history and lifestyle.17 The HPFS began in 1986 when 51 529 male health professionals (dentists, optometrists, pharmacists, podiatrists, and veterinarians), aged 40 to 75 years, answered a similar mailed questionnaire.18 Follow-up questionnaires are mailed to the participants in both studies every 2 years to update information on potential risk factors for chronic diseases and to ascertain whether major medical events have occurred. The CPS-II Nutrition Cohort comprises 86 404 men and 97 786 women, aged 50 to 79 years, from 21 states with population-based cancer registries who completed a mailed questionnaire in 1992 to investigate the relation between diet and other lifestyles factors and the risk of incident cancer.19 Similar questionnaires were sent in 1997 and every 2 years afterward to update exposure information and newly diagnosed diseases. The MEC study consists of 96 937 men and 118 843 women, aged 45 to 75 years at baseline, living in Hawaii and California (primarily Los Angeles) and mainly from the following 5 self-reported racial/ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and white.20 From 1993 to 1996, participants entered the cohort by completing a self-administered mailed questionnaire. Additional questionnaires were mailed to the participants at 5-year intervals. The NIH-AARP included 340 148 men and 227 021 women, aged 50 to 71 years, residing in 1 of 6 states or 2 metropolitan areas with high-quality cancer registries.21 The participants completed a mailed food frequency questionnaire at baseline in 1995-1996. About two-thirds of participants completed a supplementary risk factors questionnaire in 1996. All studies included were reviewed and approved by the institutional review board of the institution at which each study was conducted.
Follow-up of ALS in the CPS-II Nutrition Cohort, MEC, and NIH-AARP was through a search of the National Death Index. Vital status of the participants in these studies was determined by automated linkage with the National Death Index. The underlying and contributing causes of death were coded according to the International Classification of Diseases, Ninth Revision. All individuals with code 335.2 (motor neuron disease) listed as the underlying or contributing cause of death were considered to have had ALS. In a previous validation study,14 it was found that ALS was the primary diagnosis in virtually all instances in which code 335.2 was listed as a cause of death.
In the NHS and the HPFS, we also documented incident ALS. In each biennial follow-up questionnaire, participants were asked to report a specific list of medically diagnosed conditions (initially not including ALS) and “any other major illness.” Amyotrophic lateral sclerosis was then added to the list of specific conditions in 1992 for the NHS cohort and in 2000 for the HPFS cohort, as well as on each subsequent biennial questionnaire. For all participants who reported a diagnosis of ALS by responding to the open question on major illnesses or in answering the specific question, we requested permission for release of relevant medical records. However, because of the rapidly progressive nature of the disease, many participants with ALS died before we could send the release request for medical records; therefore, the request was sent to the closest family member. After obtaining permission, we asked the treating neurologists to complete a questionnaire to confirm the diagnosis of ALS and the certainty of the diagnosis (definite, probable, or possible) or to send a copy of the medical records. The primary diagnosis was made by a neurologist with experience in ALS diagnosis (G.L.) based on the review of medical records. We relied on the diagnosis made by the treating neurologist if the information in the medical record was insufficient or could not be obtained. When we were unable to obtain a copy of the medical record or the neurologist's questionnaire for incident self-reported ALS, we classified the participant as having possible ALS and excluded him or her from the primary analysis.
Each participant contributed person-time of follow-up from the return date of the baseline questionnaire to the date at onset of first ALS symptoms, death from ALS or any other cause, or the end of follow-up, whichever came first. The end of follow-up was June 2004 for the NHS, December 2003 for the HPFS, December 2004 for the CPS-II Nutrition Cohort, December 2002 for the MEC, and December 2005 for the NIH-AARP. Age-specific rates were calculated as the number of ALS cases divided by person-time of follow-up in each age group.
The analyses were conducted separately in each cohort using the baseline smoking information. Because of the long follow-up in the NHS, we split the cases and person-time experienced during follow-up into the following 2 uncorrelated segments: 1976 to 1990 and 1990 to 2004. In accord with the underlying theory of survival analysis, blocks of person-time in different periods are asymptotically uncorrelated, regardless of the extent to which they are derived from the same persons. Therefore, pooling the estimates from the 2 periods is equivalent to using a single period but takes advantage of the updated exposure assessment in 1990.
Cox proportional hazards regression analysis was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for ever smokers or former and current smokers compared with never smokers, adjusted for age and sex. To obtain better age adjustment, we stratified the Cox proportional hazards models by age in single years. Similar analyses were conducted by categories of pack-years smoked (≤20, 21-35, or >35 pack-years). The significance of trends was assessed by modeling the medians of each category as a continuous variable.22 We also conducted analyses using continuous variables for the mean number of cigarettes smoked per day, the total number of years smoked, and the age at smoking initiation, first including all participants and then smokers only.
Multivariable Cox proportional hazards regression analysis was used to adjust for additional potential confounders, including body mass index (BMI), physical activity, and education. There are few established risk factors for ALS. When considering potential confounders of the relation between smoking and ALS, we chose variables strongly associated with smoking for which there is also some evidence of their being risk factors for ALS. In support of these variables being reasonably well measured, each cohort validated them directly23,24 or found that they predicted disease.25-32 In addition to sex-adjusted RRs, we calculated the RRs for women and men separately. The log RRs from the 5 cohorts were pooled using a random-effects model and were weighted by the inverse of their variances.
Interactions between smoking status and baseline age (≤ or > the median) were explored as multiplicative terms in the Cox proportional hazards models in each cohort, and significance was ascertained using the likelihood ratio test. We performed similar analyses for other potential modifiers such as vitamin E and vitamin C supplement intake in each of the cohorts and sex in the CPS-II Nutrition Cohort, MEC, and NIH-AARP cohorts. To minimize the possibility of including participants who already had symptoms of ALS at the time of completing the baseline questionnaire, we conducted additional analyses that excluded the first 4 years of follow-up.
Most analyses were performed using a commercially available statistical software package (SAS version 9.1; SAS Institute Inc, Cary, North Carolina). The estimation of pooled estimates was calculated using another software package (STATA version 9; StataCorp LP, College Station, Texas).
Table 1 gives the study-specific characteristics and smoking history of the 5 cohorts at baseline. Follow-up time ranged from 9 years in the MEC to 18 years in the HPFS. In total, 832 participants had ALS among 562 804 men and 556 276 women, after applying study-specific exclusions. Among those with ALS, 16 (15 in the NIH-AARP and 1 in the HPFS) with missing information about smoking status were excluded from the analyses. The proportion of ever smokers was lowest (42.5%) among women in the MEC study and was highest (69.2%) among men in the MEC study. In each cohort, smokers were similar to nonsmokers in terms of body mass index, physical activity, and education (Table 2). The rates of ALS in the 5 cohorts combined increased with age, were consistently higher in men than women for each age group (Figure 1), and are similar to the age- and sex-specific ALS mortality rates for the United States33,34 and Europe.35
Participants who had ever smoked cigarettes at baseline had an increased risk of ALS compared with never smokers (Table 3). In the age- and sex-adjusted analysis, the pooled RRs were 1.44 (95% CI, 1.23-1.68; P < .001) for former smokers and 1.42 (95% CI, 1.07-1.88; P = .02) for current smokers compared with never smokers. The pooled RRs for smokers were slightly higher in female smokers than in male smokers, but the difference was not significant (P = .40 for interaction). When the data in the first 4 years of follow-up were excluded to minimize the potential influence of latent diseases on smoking reported at baseline, the pooled RRs were almost identical to those aforelisted (age- and sex-adjusted RR, 1.38; 95% CI, 1.09-1.77; P = .009 for ever smokers compared with never smokers). No significant interactions were found between smoking and the use of vitamin E or vitamin C supplements (P > .05).
In analyses based on pack-years smoked, the RR of ALS was 1.31 for 20 or fewer pack-years smoked, 1.71 for 21 to 35 pack-years, and 1.43 for more than 35 pack-years (Table 3). Despite the fact that ALS risk did not increase monotonically with pack-years smoked, the overall test for linear trend was significant (P = .001). Adjustment for body mass index, education, and physical activity did not materially affect the pooled estimates. The mean number of cigarettes smoked per day and the duration of smoking were positively associated with ALS when examined independently rather than combined into pack-years: the RR increased by 10% for each increment of 10 cigarettes smoked per day and by 9% for each 10 years of smoking (Figure 2). The association between years smoked and ALS was not modified by age at baseline (P = .44).
Because the aforelisted significant trends in analyses on pack-years smoked, the mean number of cigarettes smoked per day, and duration of smoking could be driven by inclusion of never smokers, we conducted further analyses restricted to ever smokers. In these analyses, pack-years smoked was not significantly associated with ALS risk (P = .60) (Table 3). Similarly, ALS risk was not significantly related to the number of cigarettes smoked per day (P = .36) or to the duration of smoking (P = .94). The only aspect of smoking behavior that remained predictive of ALS risk was age at smoking initiation; a younger age was associated with a higher risk of ALS (pooled RR, 1.11; 95% CI, 1.01-1.22; P = .03 for each 5 years younger at initiation) (Figure 3).
In this prospective study, cigarette smoking was associated with a significantly higher risk of ALS. Significant trends in the risk of ALS were observed with the duration of smoking and the number of cigarettes smoked per day, but these trends were largely driven by the low ALS risk among never smokers. Among individuals who ever smoked, the risk of ALS increased with decreasing age at smoking initiation but not with duration or intensity of smoking.
The strengths of the present study include the prospective design and the many participants with ALS. These cohorts are more likely to be representative of the whole spectrum of patients with ALS, 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 NIH-AARP cohorts as a proxy for ALS incidence. However, we assume that mortality is a reasonable surrogate for incidence because the median survival after ALS diagnosis (1.5-3 years) is short.2,37-39 Death certificates have been estimated to accurately identify 70% to 90% of ALS or motor neuron diseases–related deaths40-43; therefore, bias is unlikely unless the underreporting is strongly related to smoking. In addition, the 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 similar results. Although the study population was not chosen to be representative of the US population, the ALS mortality rates among participants in these 5 cohorts are comparable to those among the US population of similar age and sex.33,34 Baseline cigarette smoking information was used in the analysis because the questionnaire for the period of this analysis in the MEC and the NIH-AARP was administered only once; therefore, changes in cigarette smoking during the follow-up period were not captured. Although 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 study6 in Washington State, investigators reported an odds ratio of 2 (95% CI, 1.3-3.2) for the broad smoking category of ever smokers compared with never smokers. They also found a significant increase in the risk of ALS among those with more pack-years smoked and longer duration of smoking. In a case-control study5 in New England, cigarette smoking was associated with a significant 70% increase in ALS risk. However, this study did not find a dose response across pack-years smoked or duration of smoking. A case-control study7 in the Netherlands that included 364 cases found odds ratios 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 with never smokers. Among smokers, no dose response for pack-years smoked was observed. In 2004, Weisskopf et al14 reported that mortality from ALS in the CPS-II Mortality Cohort (the parent cohort for the 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), indicating a possible sex difference in the determinants of ALS. We did not find significant sex differences in the association between cigarette smoking and ALS. In a 2009 analysis of the multicenter European Prospective Investigation Into Cancer and Nutrition cohort, current smokers had approximately a 2-fold increase in ALS rates compared with 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).16 The authors also reported a dose response across the number of years spent smoking but not the pack-years smoked.
Several possible mechanisms by which cigarette smoking might influence the risk of ALS have been suggested, including direct neuronal damage from nitric oxide or other components of cigarette smoke44 (such as residues of pesticides used in tobacco cultivation45) or from 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 reported in 2008 to be associated with an increased risk of ALS.48 Inhibition of vascular endothelial growth factor 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 smoked and ALS risk would have been missed in our study. Possible explanations for the lack of a biological gradient include the following: (1) smoking is only relevant at a young age, perhaps during adolescence when the body is growing and motor neurons are under additional stress; (2) smoking may act in genetically or otherwise susceptible individuals by triggering an autoimmune or otherwise self-perpetuating neurodegenerative process that then runs its course independent of smoking behavior; (3) long-term heavy-smoking survivors are a selected group with low genetic susceptibility to ALS; or (4) one or more of several hundred chemicals contained in tobacco smoke are 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 low risk of Parkinson disease among smokers.50 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 5 cohorts of US men and women, 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. 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.
Correspondence: Éilis J. O’Reilly, ScD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 (firstname.lastname@example.org).
Accepted for Publication: April 21, 2010.
Author Contributions: Drs Wang and O’Reilly contributed equally to this work. Drs Wang, O’Reilly, and Ascherio had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Ascherio. Acquisition of data: Logroscino, McCullough, Thun, Schatzkin, Kolonel, and Ascherio. Analysis and interpretation of data: Wang, O’Reilly, Weisskopf, and Ascherio. Drafting of the manuscript: Wang and O’Reilly. Critical revision of the manuscript for important intellectual content: Weisskopf, Logroscino, McCullough, Thun, Schatzkin, Kolonel, and Ascherio. Statistical analysis: Wang, O’Reilly, and Ascherio. Obtained funding: Ascherio. Administrative, technical, and material support: O’Reilly, Weisskopf, McCullough, Thun, Schatzkin, and Kolonel.
Financial Disclosure: None reported.
Funding/Support: This work was supported by grant R01 NS045893 from the National Institute of Neurological Diseases and Stroke (Dr Ascherio).
Role of the Sponsors: The sponsors had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
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