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ALZHEIMER DISEASE MAY BE LESS FREQUENT IN HEAVY SMOKERS

San Diego—People who smoke one pack of cigarettes a day or more may be less likely to get Alzheimer disease than are those who smoke less heavily or those who never smoked, reported investigators here at the American Neurological Association Annual Meeting. However, Sara M. Debanne, PhD, who led the study, stressed that this finding should not be viewed as the final word on a longstanding controversy with years of contradictory results.

The results are different depending on the measures researchers assess, she pointed out. “If you follow smokers and non-smokers for the possible development of Alzheimer disease, most studies show that cigarette smoking increases the risk of Alzheimer disease,” Dr. Debanne, Professor of Epidemiology and Biostatistics at Case Western Reserve University in Cleveland, said in an interview.

“But if you choose people with and without Alzheimer disease and review their histories to see if they are smokers or not, it appears that fewer smokers have Alzheimer disease.” She and her co-investigators wanted to gain insight into the contradictory findings.

STUDY PROTOCOLS

The investigators conducted a case-control study and quantified the smoking history of the participants by pack-years. [A pack-year provides investigators with a tool for assessing the life-long dose of tobacco to which a smoker is exposed. For example, if someone smoked one pack daily for a year, the dosage would be one pack-year. Some who smoked two packs daily for 20 years would have an exposure of 40 pack-years.]

The investigators compared 315 patients with Alzheimer disease to two control groups: 394 were acquaintances of the cases; 176 were randomly selected from a Medicare database.

Figure

Heavy smokers – those with at least 20 pack-years – were 70 percent less likely to acquire Alzheimer disease.

The investigators controlled for age, education, sex, as well as the apolipoprotein e4 genotype, the gene implicated as a risk factor for Alzheimer disease. The investigators recoded the acquaintances into six ordinal classes based on the distribution of pack-years.

Among both control groups, there was a trend among smokers toward a reduction in risk of Alzheimer disease (with p = 0.045). They also reported that the heavy smokers – those with at least 20 pack-years – were 70 percent less likely to acquire Alzheimer disease.

At this point, a conclusive study to resolve the contradictory findings for Alzheimer disease and smoking has not yet been conducted, Dr. Debanne said. She suggested that evaluating smoking as a prognostic factor – examining its role in affecting the course of disease – rather than a predictive factor – determining whether it leads to disease – may help resolve the dilemma. “If future research confirms this role for smoking, it would explain the years of contradictory findings,” she said in an interview. She and her investigative team plan next to test whether smoking is a prognostic factor rather than a risk factor for Alzheimer disease.

“As a prognostic factor, smoking would not influence the onset of Alzheimer disease, but it would alter the course of disease if it develops, by accelerating the disease process,” Dr. Debanne explained in a separate e-mail to Neurology Today.

“The key assumption would be that smoking does not affect the probability of acquiring Alzheimer disease, but that it shortens the interval between the (unrecognized) onset of disease and the onset of symptoms that lead to diagnosis, Dr. DeBanne added.

“Because of the difference in the expected length of time between onset and diagnosis for smokers and non-smokers, it is likely that more non-smokers would die with undiagnosed Alzheimer disease,” she said, “giving smoking the appearance of a risk factor for the occurrence of Alzheimer symptoms.”

CASE-CONTROL: A STARTING POINT

“These are interesting preliminary findings,” said Charles DeCarli, MD, in a phone interview. Dr. DeCarli, who was not involved in the study, is Professor of Neurology at the University of California-Davis, where he is the Director of the Alzheimer Disease Center and the Imaging of Dementia and Aging Laboratory.

“The case-control approach is always considered a beginning, and this sample is at the edge of being representative,” he said. “There are only 315 Alzheimer disease patients.” Further, since controls in one group were acquaintances, their smoking-related risks could be environmentally influenced, depending on whether or not they were spouses or had any other relationship that would cause them to share living space with the cases or otherwise spend significant amounts of time with them.

When the investigators undertake the next step, a five-to-one ratio of controls to cases would show more clearly any role that smoking plays in cases, he said. That ratio is more the typical difference between cases and controls in this type of epidemiologic study, Dr. DeCarli said.

OTHER DIRECTIONS FOR RESEARCH

The investigators should also assess the effect-size of smoking, he added, so that the magnitude of any statistical significance would be more discernible. Even so, the goal may be elusive, he said. “Understanding the role of smoking and Alzheimer disease is tough,” he said. “Smoking is associated with so many other diseases, including stroke, which may complicate the diagnosis of Alzheimer disease.”

Another barrier to understanding the relationship between smoking and Alzheimer disease is that “smoking could not only cause other diseases but also shortens your life span,” he said. “Smokers may die before they get Alzheimer disease.”

Case-control studies that are age-matched, as Dr. Debanne and colleagues undertook, are one way to resolve the dilemma, he said. These concerns do not detract from the value of attempting to assess the relationship between smoking and Alzheimer disease, he said. “When it all gets hashed out, even if it doesn't necessarily bear fruit, the investigation is worth doing,” Dr. DeCarli said.

“One of the advantages of a cohort study is that you follow them longitudinally,” he said. “It would be worth evaluating other case-controls with larger numbers to determine if looking for the relationship between smoking and Alzheimer disease bears fruit. It could also be worthwhile to look at ethnic and gender issues. A larger sample would open up the opportunity to finding interrelationship among other factors.”

Figure

Dr. Sara M. Debanne: “If you follow smokers and non-smokers for the possible development of Alzheimer disease, most studies show that cigarette smoking increases the risk of Alzheimer disease. But if you choose people with and without Alzheimer disease and review their histories to see if they are smokers or not, it appears that fewer smokers have Alzheimer disease.”

It would also be worthwhile to draw a sample from another geographic area with a different rate of adult smokers, Dr. DeCarli said. He noted that the relationship between smoking and Alzheimer disease may, or may not, change in places with high versus low rates of smoking.

ARTICLE IN BRIEF

  • ✓ In a case-control study, investigators reported that there was a trend among smokers toward a reduction in risk of Alzheimer disease. They also reported that the heavy smokers were 70 percent less likely to acquire Alzheimer disease.