Critique 087: Smoking increases, while alcohol consumption may decrease, the risk of amyotrophic lateral sclerosis (ALS) — 8 August 2012

de Jong SW, Huisman MHB, Sutedja NA, van der Kooi, AJ, de Visser M, Schelhaas HJ, Fischer K, Veldink JH, van den Berg LH.  Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: A population-based study.  Am J Epidemiol 2012;176:233–239

Authors’ Abstract

Smoking has been posited as a possible risk factor for amyotrophic lateral sclerosis (ALS), but large population-based studies of patients with incident disease are still needed.  The authors performed a population-based case-control study in the Netherlands between 2006 and 2009, including 494 patients with incident ALS and 1,599 controls.   To prove the relevance of population-based incidence cohorts in case-control studies, the authors compared results with those from cohorts including patients with prevalent ALS and referral patients.  Subjects were sent a questionnaire.

Multivariate analyses showed an increased risk of ALS among current smokers (odds ratio = 1.38, 95% confidence interval (CI): 1.02, 1.88) in the incident patient group only.  Cox regression models showed that current smoking was also independently associated with shorter survival (hazard ratio = 1.51, 95% CI: 1.07, 2.15), explaining the lack of association in the prevalent and referral patient groups.  Current alcohol consumption was associated with a reduced risk of ALS (incident patient group: odds ratio = 0.52, 95% CI: 0.40, 0.75).  

These findings indicate that current smoking is associated with an increased risk of ALS, as well as a worse prognosis, and alcohol consumption is associated with a reduced risk of ALS, further corroborating the role of lifestyle factors in the pathogenesis of ALS.  The importance of population-based incident patient cohorts in identifying risk factors is highlighted by this study.

Forum Comments

Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurological disease, for which there is no known effective therapy.  While a small percentage of cases have a demonstrated genetic component in its development, most cases are unexplained, and very little data on potential environmental risk factors are available. 

Forum reviewers thought that this was a well-done and important paper, as it is a population-based analysis, with almost 500 cases of ALS.  Familial cases of ALS, which  generally make up less than one quarter of cases, were excluded, so the paper is based on the more common sporadic type of disease.  The paper concludes that the risk of ALS is increased by smoking, which has been suggested by previous studies.  In addition, it suggests that moderate alcohol consumption is associated with a considerably lower risk of ALS.

Specific Comments on paper:  The increased risk of ALS among smokers is consistent with some earlier studies, including a recent pooled analysis by Wang et al.¹  On the other hand, forum reviewers were surprised by the association between alcohol and ALS, especially the magnitude of the difference in risk of ALS between alcohol consumers and never drinkers: the risk among drinkers was about one half that of non-drinkers.  Said one reviewer: “The results in this study are astonishing in this mysterious disease.  One should expect that alcohol, as a toxic agent, rather should contribute to the development of ALS than to prevent it.  The lower risk among drinkers compared with non-drinkers is remarkable.”  Stated another reviewer: “I find this paper interesting and reliable.  I am struck by the number of cases the authors were able to collect.  It is probably irrelevant, but I am reminded of the helpfulness of alcohol to those suffering from essential tremor, presumably an unrelated genetically determined neurological disorder.”  

Forum member Andrew Waterhouse stated: “With the others, I am struck by the very strong beneficial effect of alcohol consumption in reducing the risk of ALS.  Within the 95% confidence interval, the highest risk for drinkers would be 75% of those who were non-drinkers, which is remarkably low.  As this is such a rare disease, it makes no sense to recommend alcohol consumption to avoid it.  But the dramatic impact, and the lack of demonstrated biological mechanism, suggests this is an area sorely needing attention and liable to yield valuable insight.  I suspect that an understanding of this mechanism(s) would help shed light on how alcohol affects other diseases.”

As pointed out by Forum reviewer Yuqing Zhang (see below), the fact that in this study the incidence of ALS, but not survival of subjects with ALS, was lower among drinkers than non-drinkers may relate to what is known as “collider bias.”  However, the lower risk of incident ALS among drinkers would not be affected by such bias, and the odds ratios for incident cases and prevalent cases were very similar. 

Potential mechanisms of effect:  Forum reviewers cautioned that this is only one study, and must be replicated before getting too excited about the results, especially since the mechanisms of such an effect are not known.  Esposito et al² reported that lyophilized red wine was associated with prolonged survival in an animal model of ALS, and Amodio et al³ found that red wine prevents neuronal apoptosis in a mouse model.  However, familial ALS cases were not included in the present study, and it is unclear how such animal studies relate to the more common random type of disease.  Also, the authors of the present paper state that they did not find a significant difference between the percentage of cases (58%) and controls (68%) who reported that they consumed red wine. 

Moderate drinking has consistently been shown to reduce the risk of dementia, as recently summarized by Kim et al.⁴  But even with dementia, the mechanisms are unclear, as described in a recent review of this topic by this forum.⁵  Potential mechanisms by which alcohol consumption could reduce the risk of ALS remain even more obscure.

Reasons for differences in effects of alcohol on the occurrence of ALS and its course:  Forum reviewer Yuqing Zhang explains why there may be differences in the effects of alcohol on the occurrence and on the course of ALS.  “If alcohol consumption decreases the risk of ALS (which was reported in this paper), one would expect that it should also decrease mortality among patients with ALS.  In the current paper the authors did not find such an association (i.e., no association between alcohol consumption and death from ALS). 

“This apparent discrepancy may relate to what is known as “collider bias”: If an exposure relates to the development of a disease, the course of the disease after diagnosis may differ between people who got the disease despite the protective factor versus those who were not exposed to the protective factor.  For example, among patients with ALS who drank alcohol prior to getting the diagnosis, they must have been exposed to other risk factors for ALS which overcame any protective effect of alcohol: the two groups may differ when studying the progression of the disease after diagnosis.  If these other factors are not controlled for, it will drive any association between alcohol and mortality from ALS towards the null. 

“This kind of bias has been discussed, especially recently, by many investigators, including a description of such bias in studying exposures for incidence and progression of knee osteoarthritis.”⁶  A similar phenomenon has been shown for genetic factors affecting the risk of dementia.⁷  Other studies show that obesity is a strong risk factor for the development of most cardiovascular diseases, but is less associated with the subsequent course of people who have already become fat.  Such differences do not detract from the markedly lower risk of ALS among drinkers found in this study.

References

1.  Wang H, O’Reilly ÉJ, Weisskopf MG, Logroscino G, McCullough ML, Thun MJ, Schatzkin A, Kolonel LN, Ascherio A.  Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of 5 prospective cohorts.  Arch Neurol 2011;68:207-213.

2.  Esposito E, Rossi C, Amodio R, Di Castelnuovo A, Bendotti C, Rotondo T, Algeri S, Rotilio D.  Lyophilized red wine administration prolongs survival in an animal model of amyotrophic lateral sclerosis.  Ann Neurol 2000;48:686-687.

3.  Amodio R, Esposito E, De Ruvo C, Bellavia V, Amodio E, Carruba G.  Red wine extract prevents neuronal apoptosis in vitro and reduces mortality of transgenic mice.  Ann N Y Acad Sci. 2006 Nov;1089:88-97.

4.  Kim JW, Lee DY, Lee BC, Jung MH, Kim H, Choi YS, Choi I-G.  Alcohol and cognition in the elderly: A review.  Psychiatry Investig 2012;9:8-16;  On-line: http://dx.doi.org/10.4306/pi.2012.9.1.8

5.  Recent Forum summary on mechanisms:  https://alcoholresearchforum.org/critique-081-alcohol-intake-in-the-elderly-affects-risk-of-cognitive-decline-and-dementia-22-may-2012/

6.  Zhang Y, Niu J, Felson, DT, et al.  Methodologic challenges in studying risk factors for progression of knee osteoarthritis.  Arthritis Care & Research 2010;62:1527–1532.  DOI 10.1002/acr.20287

7.  Glymour MM.  Invited Commentary: When bad genes look good—APOE*E4, cognitive decline, and diagnostic thresholds.  Am J Epidemiol 2007;165:1239–1246.

Forum Summary

A population-based case-control study of the rare but devastating neurological disease amyotrophic lateral sclerosis (ALS) has shown that the risk of such disease is increased among smokers, as has been shown previously.  However, surprisingly, the risk of ALS was found to be markedly lower among consumers of alcohol than among abstainers. 

Forum reviewers thought that this was a well-done and important paper, as it is a population-based analysis, with almost 500 cases of ALS, a very large number of cases for this rare disease.  They were especially struck by the magnitude of the difference in risk of ALS between alcohol consumers and never drinkers: the risk among drinkers was about one half that of non-drinkers.  Said one reviewer: “The results in this study are astonishing in this mysterious disease.  One should expect that alcohol, as a toxic agent, rather should contribute to the development of ALS than to prevent it.  The lower risk among drinkers compared with non-drinkers is remarkable”  

Forum reviewers cautioned that the results of this paper should not be used to prompt people to consume alcohol just to prevent ALS, as it is such a rare disease.  However, this paper presents important data that could help scientists understand the etiology of ALS and perhaps other more common diseases. 

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Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:

Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA

Giovanni de Gaetano, MD, PhD, Research Laboratories, Catholic University, Campobasso, Italy

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark