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Question Is there an association between cigarette smoking and Alzheimer's disease (AD)?
Design
Cohort analytic study with follow up for a mean of 2 years.
Setting
Community based study in northern Manhattan, New York City, USA.
Participants
1062 elderly Medicare recipients (mean age 75 y, 69% women) without dementia at start of study.
Assessment of risk factors
A structured risk factor questionnaire was developed and used at baseline to determine exposure to putative risk factors related to dementia. 3 sets of questions dealt with smoking history. General health and function, years of formal education, and medical history were determined. A physical, neurological, and neuropsychological examination were also done. APOE genotype was determined for each participant.
Main outcome measure
Blinded diagnosis of AD using standardised clinical assessments at annual visits.
Main results
142 participants were diagnosed with AD during follow up. After adjustment for education and ethnicity and using never smoked as the reference, a previous history of smoking was not associated with AD (table⇓). Those who were current smokers had an increased risk of developing AD (table⇓). The association between current smoking and AD decreased in the presence of APOE ε4 but not for current smokers without APOE ε4 (table⇓).
Relative risk (RR) of developing Alzheimer's disease by smoking history
Conclusions
There was an increased risk of developing Alzheimer's disease among current smokers. APOE ε4 slightly modified this association.
Commentary
The association between smoking and AD is controversial. Several early case control studies suggested that smoking is protective against AD. 1 Because AD is associated with reduced acetylcholine activity, perhaps nicotine delays the disease. These studies, however, may be biased because only very fit smokers, with a genetic advantage, survive into later life. 2 To some extent, this study by Merchant et al and the recently published prospective Rotterdam Study,3 have settled the controversy. Both studies found that present smokers are at roughly double the risk of developing AD than those who have never smoked.
Interestingly, the study by Merchant et al (but not the Rotterdam Study) found that former smokers may be at a reduced risk (although the result was not statistically significant). Because having an APOE ε4 allele is a risk factor for developing AD and vascular disease, there may be an interaction between smoking, APOE ε4, and AD. Again, both studies found that smoking is more of a risk factor for those without APOE ε4. This may reflect, however, the fact that smokers with APOE ε4, who survive into later life, are a distinct group.
The main limitation of these studies is that they do not have necropsy confirmation of diagnosis. Smokers may be developing vascular dementia which is misdiagnosed as AD. Also, smoking is a marker for other factors (such as poverty or alcohol use), which Merchant et al have tried to take into account by adjusting for education and ethnicity.
The clinical message is do not recommend smoking to any of your patients, at any age. There is some good news for smokers: giving up smoking reduces your risk of developing AD. The bad news is: otherwise smokers can only reduce their risk of AD by dying of something else first.
Footnotes
Sources of funding: US Federal Government; the Charles S Robertson Memorial Gift for Alzheimer's Disease from the Banbury Fund; Blanchette Hooke Rockefeller Fund.
For correspondence: Dr R Mayeux, G H Sergievsky Center, 630 West 168th Street, Columbia University, New York, NY 10032, USA. Fax +1 212 305 2518.