Smoking a Risk Factor, Alcohol Protective, in ALS

Pam Harrison

August 24, 2012

August 24, 2012 — Cigarette smoking is independently associated with increased risk — and alcohol consumption with significantly decreased risk — of developing amyotrophic lateral sclerosis (ALS), according to a prospective, population-based case-control study by Dutch investigators.

Sonja de Jong, from the University Medical Center Utrecht, The Netherlands, and multicenter colleagues found that current smoking increased the risk for ALS by 38% in an incident population diagnosed with ALS on or after January 1, 2006, compared with individuals who had never smoked.

Alcohol consumption of any kind decreased the risk of developing ALS by 48% relative to those who had never consumed alcohol in the same incident population, as well as by 65% in the "prevalent" population diagnosed with ALS before January 1, 2006, and by 57% in the combined incidence and prevalence groups plus a separate group of patients diagnosed with sporadic ALS at the Utrecht Center between January 1, 2001, and December 31, 2005.

"There have been many methodological shortcomings with previous studies linking different risk factors with ALS, which is why the field is so confusing and even contradictory," Leonard van den Berg, MD, told Medscape Medical News. "So we used a population-based cohort with no selection bias and found a strong protective effect of alcohol against ALS, which surprised us and for which we have no explanation."

The study was published online July 11, 2012 in American Journal of Epidemiology.

Contrasting Results

In an effort to provide more robust evidence supporting the link between smoking and ALS, Dutch investigators carried out the Prospective ALS Study in The Netherlands between 2006 and 2009.

The study included 494 patients with incident ALS and 1599 controls. Another 255 patients who were recruited into the study had been diagnosed with ALS before January 2006, and those who were still alive were classified as "prevalent" patients.

All incident and prevalent patients, together with a combined referral group diagnosed with ALS at the Utrecht Center between January 1, 2001, and December 31, 2005, brought the total number of patients with ALS included in the study to 937.

In incident patients, multivariate analyses showed increased risk for ALS among current smokers, with an odds ratio (OR) of 1.38. ORs were similar for men (at 1.48) and for women (at 1.47).

In contrast, no significant association was observed between current smoking and ALS risk in either the prevalent patient group or the total population.

Information on vital capacity was available for 61% of the total cohort of patients with ALS at the time of diagnosis. As might be expected, decreased vital capacity was significantly associated with shorter survival (P = .026), and in patients with decreased vital capacity, current smoking was associated with a worse prognosis, with a hazard ratio of 1.51.

Premorbid current smoking in particular was associated with the development of ALS and might act as a "trigger" in a multifactorial cascade, as investigators suggest.

Current alcohol consumption was found to be independently associated with reduced risk for ALS in all 3 patient groups — incident, prevalent, and total. No specific effect of drinking red wine could be identified, as has been suggested by previous studies.

Also, no significant interaction between smoking and alcohol consumption was noted, nor was alcohol consumption associated with survival or age at disease onset.

Table. Cigarette Smoking and Alcohol Consumption Among ALS Patients


Adjusted Odds Ratio

Cigarette Smoking Incident Patients Prevalent Patients Total Population
Never 1 1 1
Current 1.38 0.83 1.26
Alcohol Consumption Incident Patients Prevalent Patients Total Population
Never drinker 1 1 1
Current drinker 0.52 0.35 0.43

ALS, amyotrophic lateral sclerosis.

Variety of Mechanisms

Smoking could increase the risk of developing ALS through a variety of mechanisms, including inflammation, oxidative stress, and neurotoxicity caused by heavy metals and other chemicals in cigarette smoke.

Alcohol may possess neuroprotective properties but, as Dr. van den Berg noted, investigators have no real explanation as to why alcohol appeared to be so protective against ALS, and the connection between the 2 points to new pathways for explanation of the cause of the disease.

"We tell our patients with ALS to stop smoking because of potential pulmonary problems they may develop later on in the disease, but alcohol does not harm them, so if they ask, we tell them they can go ahead and have that glass of wine," he added.

Forum Review

Several investigators from the International Scientific Forum on Alcohol Research have reviewed the population-based study.

Collectively, forum reviewers indicated that this was a "well-done and important paper." Because it excluded familial cases of ALS, the population also represented the more common sporadic type of disease, making results more generalizable to the ALS population overall.

Previous studies had suggested that smoking increases ALS risk, as pointed out by reviewers, so results from this study add to preexisting evidence.

On the other hand, reviewers expressed surprise at the magnitude of the association between alcohol and ALS, the risk among drinkers being almost half that of nondrinkers.

"One should expect that alcohol, as a toxic agent, rather should contribute to the development of ALS than prevent it," stated one reviewer, Andrew Waterhouse, PhD, from the University of California in Davis.

"The dramatic impact [of alcohol on ALS] and the lack of demonstrated biological mechanisms suggest that this is an area sorely needing attention and liable to yield valuable insight," he added.

Although cautioning that findings must be replicated, especially because the potentially protective effects of alcohol against ALS are unknown, reviewers note that a previous report from Esposito and associates (Ann Neurol. 2000;48:686-687) found that lyophilized red wine was associated with prolonged survival in an animal model of ALS, and in another study, Amodio and colleagues (Ann N Y Acad Sci. 2006;1089:88-97) found that red wine prevents neuronal apoptosis in a mouse model.

"However, familial ALS cases were not included in the present study," reviewers observe, "and it is unclear how such animal studies relate to the more common, random type of disease."

This study was supported by the Prinses Beatrix Fonds and The Netherlands ALS Foundation. The authors and reviewers have disclosed no relevant financial relationships.

Am J Epidemiol. 2012;176:233-239. Abstract


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