To examine the relationship between smoking and Alzheimer's disease (AD) after controlling for study design, quality, secular trend, and tobacco industry affiliation of the authors, electronic databases were searched; 43 individual studies met the inclusion criteria. For evidence of tobacco industry affiliation, http://legacy.library.ucsf.edu was searched. One fourth (11/43) of individual studies had tobacco-affiliated authors. Using random effects meta-analysis, 18 case control studies without tobacco industry affiliation yielded a non-significant pooled odds ratio of 0.91 (95% CI, 0.75–1.10), while 8 case control studies with tobacco industry affiliation yielded a significant pooled odds ratio of 0.86 (95% CI, 0.75–0.98) suggesting that smoking protects against AD. In contrast, 14 cohort studies without tobacco-industry affiliation yielded a significantly increased relative risk of AD of 1.45 (95% CI, 1.16–1.80) associated with smoking and the three cohort studies with tobacco industry affiliation yielded a non-significant pooled relative risk of 0.60 (95% CI 0.27–1.32). A multiple regression analysis showed that case-control studies tended to yield lower average risk estimates than cohort studies (by −0.27 ± 0.15, P = 0.075), lower risk estimates for studies done by authors affiliated with the tobacco industry (by −0.37 ± 0.13, P = 0.008), no effect of the quality of the journal in which the study was published (measured by impact factor, P = 0.828), and increasing secular trend in risk estimates (0.031/year ± 0.013, P = 0.02). The average risk of AD for cohort studies without tobacco industry affiliation of average quality published in 2007 was estimated to be 1.72 ± 0.19 (P< 0.0005). The available data indicate that smoking is a significant risk factor for AD.
