Smoking and Alzheimer's disease

THE LAST GREAT TOBACCO CLAIM
by Phantomimic All rights reserved © RAGG

For decades the tobacco industry mustered all its financial, legal and political clout to fight tooth and claw against the concept that their product was harmful. Only in 1998 with the release of the previously secret internal tobacco industry documents, as a result of the Master Settlement Agreement, were the types of strategies the industry employed finally revealed to the general public. The main goal was to raise controversy and make any antitobacco evidence look tentative. To this end, the tobacco industry sponsored research designed to produce findings that were favorable to its position while often hiding the extent of its involvement. The industry also disseminated favorable research to the lay press and policy makers while suppressing research that did not support its position. Fortunately nowadays it is widely acknowledged as a rock solid fact that smoking is harmful to a person's health. Most people now know that smoking increases the risk of lung cancer. But smoking also increases the risk of cardiovascular and cerebrovascular problems, atherosclerosis and stroke. For these reasons, smoking would be expected to be a risk factor when it comes to Alzheimer's disease. In Alzheimer's disease the metabolism of the brain is compromised. Adding on the myriad of health problems due to smoking would certainly not be considered to be helpful. This is especially relevant considering that Alzheimer's disease is most common in elderly people who often have a host of age-related health problems. Indeed, as expected, several studies have found that smoking increases the risk of Alzheimer's disease. But there was a paradox.

Among the signaling systems that are compromised in the brain of Alzheimer's patients is the so called cholinergic system and there are receptors within this system that can be stimulated by nicotine, which is present in tobacco. Thus, in theory, nicotine could "boost" this system to compensate (at least for a certain amount of time) for its deterioration in Alzheimer's disease. Nicotine has also been found to increase alertness and enhance learning and memory. So, the argument grew that cigarettes, being in effect a nicotine delivery system, could be helpful in Alzheimer's disease. Indeed, several studies have found that smoking in different contexts reduces the risk of Alzheimer's disease and this notion has made its way to the lay press and cyberspace. But these claims have been controversial as many consider that the harmful chemicals in tobacco would likely outweigh any positive effects of nicotine, and even if nicotine were found to be beneficial there are safer and more efficient means of delivering it to the body than through cigarette smoke. However, the fact remains that, for the majority of people, the most common nicotine delivery vehicle is smoking. Not surprisingly the tobacco industry has funded research into this matter for the past two decades. In a recent article published in the Journal of Alzheimer's Disease by Janine Cataldo, Judith Prochaska and Staunton Glantz, researchers of the University of California, San Francisco (UCSF), the authors did something that previous researchers in the field of Alzheimer's disease had not done. Normally when you perform a statistical evaluation of the scientific literature regarding a certain topic you want to account for all the variables that can affect the outcome of the studies you are reviewing. This is called

"controlling a variable", which is important, otherwise you end up comparing apples and oranges. What the UCSF researchers did is that they "controlled" for several variables among which was the affiliation of the authors of the studies with the tobacco industry. To do this they went through thousands of previously secret tobacco industry documents and identified those studies that had authors who were involved with the tobacco industry within ten years of publication of the study. What was the result? The authors reviewed 43 studies of smoking and Alzheimer's disease that met their inclusion criteria which were: 1) the study had to be published, 2) it had to use Alzheimer's disease as the outcome (not dementia or cognitive decline), 3) use human subjects (brain tissue excluded), 4) have a measurement of smoking (i.e. ever smoker, current smoker, never smoke) and 5) have a clearly stated study design (case control or cohort study). Of these 43 studies, 11 (26%) were conducted by tobacco industry affiliated investigators but in only 3 of them was the affiliation disclosed. If all 43 studies were combined without controlling for any variables (mixing apples and oranges) the overall result was that smoking had no effect on Alzheimer's disease yielding a risk ratio of 1.05 (1 = no risk). The authors first focused on a particular type of study called a "cohort" study. This is a study where a group of smokers and non-smokers are followed over time and evaluated for the development of Alzheimer's disease. In the area of epidemiology cohort studies are widely considered the most scientifically valid type of studies. They found that when they

controlled for several variables including tobacco industry affiliation (thus separating the apples from the oranges), the risk-ratio of a current or ever tobacco smoker developing Alzheimer's disease was 1.72. In other words a current or ever smoker had a 72% higher risk of developing Alzheimer's disease than a non-smoker. The authors then focused on a second type of study called a "case control" study where a group of individuals with Alzheimer's disease is compared for "exposure to smoking" to a matched group of individuals without Alzheimer's disease. It was important to distinguish between cohort and case control studies because case control studies are more prone to bias that can underestimate the risk of Alzheimer's disease. The authors found that the case control studies with no tobacco industry affiliation yielded a nonsignificant risk ratio of 0.91, whereas the studies with tobacco industry affiliation yielded a statistically significant ratio of 0.86, meaning that smoking was found to be "protective". Finally the authors performed an evaluation of past reviews of the scientific literature investigating the relationship between smoking and Alzheimer's disease. Of the 10 systematic reviews the authors examined there were 6 reviews performed by scientists with no tobacco industry affiliation. Of these 6 reviews, 1 found no clear effect, 2 found no protective effect of smoking and 3 found smoking to be a significant risk factor. The 4 reviews performed by scientists with known tobacco industry affiliation all concluded that smoking protected against Alzheimer's disease.

So overall "type of study" and "researchers with ties to the tobacco industry" were variables associated with lower risk estimates, the latter to a much greater extent than the former, but when these variables were controlled for, a clear effect of smoking on Alzheimer's disease emerged. The fact that tobacco industry sponsored research favors the industry's position is nothing new. For example, in a 1998 evaluation by Deborah Barnes and Lisa Bero of 106 scientific literature reviews regarding passive smoking they found that the only factor associated with whether a review concluded that passive smoking is not harmful to health was whether its authors were associated with the tobacco industry. But the UCSF study described in this article and others sure to follow will hopefully mean the end to one of the last great lingering claims associated with smoking: that it is protective in Alzheimer's disease.

One last note, Ronald Reagan is one of the most visible personalities to have developed Alzheimer's disease, and he was a smoker like many celebrities of his time (although I understand he quit when he became governor of California). This is the only reason I chose his image for this article. Epidemiology is a population-based science, it cannot predict or assert whether an individual will develop or has developed Alzheimer's disease due to smoking.

References
Cataldo JK, Prochaska JJ, Glantz SA. (2010) Cigarette smoking is a risk factor for Alzheimer's Disease: an analysis controlling for tobacco industry affiliation. J Alzheimers Dis. 2010;19(2):465-80. http://www.ncbi.nlm.nih.gov/pubmed/20110594 Deborah E. Barnes and Lisa A. Bero (1998) Why Review Articles on the Health Effects of Passive Smoking Reach Different Conclusions. JAMA. 1998;279:1566-1570. http://jama.ama-assn.org/cgi/reprint/279/19/1566 Lisa A. Bero, 2005, Tobacco Industry Manipulation of Research, Public Health Reports, March–April, Volume 120, pp. 200-208. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1497700/pdf/15842123.pdf The secret tobacco industry document site has some eyebrow-raising http://legacy.library.ucsf.edu/ The picture is from Wellmedicated.com, visit the web site for some unbelievable cigarette adds from the days of yore. http://wellmedicated.com/lists/40-gorgeous-vintage-tobacco-advertisements/ These pictures were in turn taken from from SA_Steve's Flickr.com photo stream of vintage tobacco advertising. http://www.flickr.com/photos/sa_steve/sets/72157615938880840/

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