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American Journal of Epidemiology Advance Access originally published online on June 14, 2007
American Journal of Epidemiology 2007 166(4):367-378; doi:10.1093/aje/kwm116
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Smoking as a Risk Factor for Dementia and Cognitive Decline: A Meta-Analysis of Prospective Studies

Kaarin J. Anstey1, Chwee von Sanden1, Agus Salim1 and Richard O'Kearney2

1 Centre for Mental Health Research, The Australian National University, Canberra, Australia
2 School of Psychology, The Australian National University, Canberra, Australia

Correspondence to Dr. Kaarin J. Anstey, Centre for Mental Health Research, The Australian National University, Eggleston Road, Canberra, Australian Capital Territory 0200, Australia (e-mail: kaarin.anstey{at}anu.edu.au).

Received for publication December 20, 2006. Accepted for publication March 2, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors assessed the association of smoking with dementia and cognitive decline in a meta-analysis of 19 prospective studies with at least 12 months of follow-up. Studies included a total of 26,374 participants followed for dementia for 2–30 years and 17,023 participants followed up for 2–7 years to assess cognitive decline. Mean study age was 74 years. Current smokers at baseline, relative to never smokers, had risks of 1.79 (95% confidence interval (CI): 1.43, 2.23) for incident Alzheimer's disease, 1.78 (95% CI: 1.28, 2.47) for incident vascular dementia, and 1.27 (95% CI: 1.02, 1.60) for any dementia. Compared with those who never smoked, current smokers at baseline also showed greater yearly declines in Mini-Mental State Examination scores over the follow-up period (effect size (ß) = –0.13, 95% CI: –0.18, –0.08). Compared with former smokers, current smokers at baseline showed an increased risk of Alzheimer's disease (relative risk = 1.70, 95% CI: 1.25, 2.31) and an increased decline in cognitive abilities (effect size (ß) = –0.07, 95% CI: –0.11, –0.03), but the groups were not different regarding risk of vascular dementia or any dementia. The authors concluded that elderly smokers have increased risks of dementia and cognitive decline.

Alzheimer disease; cognition; dementia, vascular; meta-analysis; smoking

Abbreviations: APOE, apolipoprotein E; CI, confidence interval; RR, relative risk


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The association between smoking and risk of dementia, including Alzheimer's disease, remains unclear. Early research found that nicotine improves short-term cognitive performance (1) and inhibits amyloid formation (2). This finding suggested that smoking may be protective against dementia and that nicotine may be cognitively enhancing. More recently, this evidence has been questioned and claims made that the known negative effect of smoking on cardiovascular disease means that it is likely to be a risk factor for vascular dementia (3). Because of the increasing prevalence of dementia and the high associated burden of disease, morbidity, and disability (1), there is an urgent need to clearly identify modifiable risk factors, such as smoking, for cognitive decline and dementia.

In 2002, a systematic review of 21 case-control and eight cohort studies examining smoking as a risk factor for Alzheimer's disease found conflicting results regarding the direction of the association (4). Case-control studies suggested that smoking is protective (odds ratio = 0.74, 95 percent confidence interval (CI): 0.66, 0.84), whereas the pooled effect for the cohort studies showed an opposite effect (relative risk (RR) = 1.10, 95 percent CI: 0.94, 1.29), with a strong significant association between smoking and increased risk of Alzheimer's disease for participants who were smokers at baseline and had developed Alzheimer's disease at follow-up (RR = 1.99, 95 percent CI: 1.33, 2.98). The latter finding was based on only two studies that used true prospective cohort designs examining incidence of dementia. In addition, the review examined a diagnosis of Alzheimer's disease as the single outcome despite the putative connection between smoking and vascular dementia.

To date, there has been no known systematic review of longitudinal studies of smoking as a risk factor for the range of cognitive decline and dementias that occur in aging. When such studies associate exposure at baseline with incident dementia, and cognitive decline at follow-up, they provide information at much lower risk of bias compared with case-control studies and historical cohort studies. The growing number of reports from large-scale longitudinal studies of cognitive function and dementia now offer the opportunity to conduct such a review and to provide a stronger quantitative assessment of the effect of smoking on dementia and cognitive decline. The aim of this review was to quantitatively evaluate the association of self-reported smoking with incident dementia and cognitive decline.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Literature search
Electronic databases including PubMed (National Library of Medicine, Bethesda, Maryland; 1950 to June 2005), PsycINFO (American Psychological Association, Washington, DC; 1872 to June 2005), and Cochrane CENTRAL (John Wiley & Sons, Inc., Hoboken, New Jersey; 1800 to June 2005) were searched. The search used a combination of keywords for smoking (smoking, tobacco, nicotine) and cognition (cognit*, memory, attention, reaction time, processing speed, crystalli#ed ability, crystalli#ed intelligence, fluid ability, fluid intelligence, general mental ability OR GMA, intelligence, executive function, neuropsychological test*, mini mental state examination OR MMSE, dementia, mild cognitive impairment OR MCI), where * indicates truncation and # indicates wild card. The search was limited to English language and human studies only. Reference lists of selected publications were also hand searched for any other relevant articles.

Inclusion and exclusion criteria
To be included, studies had to have at least two occasions of measurement and report outcomes for either dementia (Alzheimer's disease, vascular dementia, or dementia; table 1) or cognitive decline. For analysis of dementia outcomes, studies were included only if they screened for dementia at baseline and had a follow-up of at least 12 months. For analysis of cognitive outcomes, data on cognitive performance had to be obtained at baseline plus at least one follow-up of at least 12 months' duration. No relevant randomized controlled trials were identified in the literature.


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  		TABLE 1. Definitions of outcomes for inclusion in the meta-analysis of smoking as a risk factor for dementia and cognitive decline

 
For both dementia and cognitive outcomes, studies had to measure exposure to smoking at baseline and analyze the association between smoking and dementia or cognitive decline to be included. Studies were excluded if they had a clinical sample (e.g., Parkinson's disease, head injury, human immunodeficiency virus) or a sample size of less than 50.

Multiple publications from a single study
Multiple publications using the same sample or study (e.g., The Rotterdam Study) were included if they examined 1) different smoking measures (e.g., one article may examine packs of cigarettes smoked per day multiplied by years of smoking (pack-years) while another may examine smoking status); 2) different cognitive outcomes (e.g., one article may examine dementia while another examined Alzheimer's disease); or 3) smoking or cognitive outcomes measures in different forms (e.g., one article examined a continuous outcome while another analyzed a categorical outcome). When there were multiple publications from a single study with the same smoking measures and outcome measures, decision rules were established for choosing one out of multiple publications. Priority was given to studies in which smoking was the key independent variable and then to more recent studies. However, it was found that for each study, only one publication provided sufficient data for inclusion in the review, except for the Washington Heights Inwood Columbia Aging Project study. For example, from the Epidemiology of Vascular Aging Study, an earlier report (5) was selected over a later study (6) because of the availability of relevant data in the former compared with the latter. For the Washington Heights Inwood Columbia Aging Project study, a more recent publication was chosen to replace an earlier study on recommendation of the authors (7, 8). Relevant publications were selected independently by two of the authors (K. A. and C. vS.), and disagreements were resolved through discussion.

Outcomes
There were seven potential study outcomes, including three for dementia and four based on cognitive measures, described in table 1. Outcomes for dementia included Alzheimer's disease, vascular dementia, or any dementia. Several studies reported results for only Alzheimer's disease as an outcome (7, 9–11), whereas others reported results for subtype(s) of dementia as well as for any dementia (12–16). Cognitive outcomes were categorized as cognitive performance at follow-up, cognitive performance change, cognitive decline, and cognitive impairment.

Data extraction
Articles were de-identified (blinded title, author(s), year of publication, and journal name) before data extraction. The following information was extracted from each article by C. vS. and was cross-checked by a second researcher: length of follow-up, description of smoking measure, description of cognitive measures, average age, percentage of males, average years of education, and, where relevant, total number of cases and noncases, measure of association (odds ratio, hazard ratio, relative risk) with its 95 percent confidence interval, and variables adjusted for in the analyses. Results from both unadjusted and adjusted analyses were extracted.

Data compilation for analysis
Authors were contacted via e-mail for any missing information. Studies used different types of comparisons within smoking status measures (including ever vs. never, current vs. former or never, current vs. never, current vs. former, former vs. never), and some studies reported smoking in pack-years defined as years of smoking the equivalent of one pack of cigarettes per day. Current smokers in these studies were defined as participants who reported they were smokers when data were collected at baseline.

When results for more than one follow-up period were reported for the same study, the estimate from the longest follow-up was selected. For studies reporting multiple statistical models with different covariates, the result with the smallest standard error of estimates was selected because it represents the most precise effect estimate from the study. For example, for the outcome of Alzheimer's disease, Moffat et al. (11) investigated three models that included smoking but differed regarding the final covariate, which was either free testosterone index, total testosterone, or sex hormone-binding globulin. The estimate for smoking was selected from the model including free testosterone index, which had the smallest standard error. For all studies, preference was given to the results adjusted for the most covariates.

Types of comparisons
Meta-analysis was conducted when more than one study was compatible in terms of the smoking measure and the outcome measure. Studies were grouped according to type of comparison and were subgrouped according to type of outcome. Studies with sufficient statistical data for analysis (obtained from articles or from successful contact with authors) were examined for compatible measures of smoking and cognitive outcomes. There were enough data to conduct comparisons of 1) current smokers versus never smokers for risk of Alzheimer's disease, vascular dementia, any dementia, and change in cognitive performance; 2) ever smokers versus never smokers for Alzheimer's disease, any dementia, and cognitive impairment; 3) former smokers versus never smokers for Alzheimer's disease, vascular dementia, any dementia, and change in cognitive performance; 4) current smokers versus former smokers for Alzheimer's disease, vascular dementia, any dementia, and change in cognitive performance; and 5) current smokers versus former or never smokers for Alzheimer's disease and cognitive decline. The only cognitive measure for which there were enough compatible data within a comparison group to analyze cognitive performance change (defined in table 1) was the Mini-Mental State Examination.

Statistical analysis
Studies with dichotomous outcomes reported effect size measures in the form of relative risks, hazard ratios, or odds ratios. A hazard ratio is the ratio of the probability of an outcome in the exposed group compared with the nonexposed group. For our review, relative risks, hazard ratios, and odds ratios were treated the same and are referred to as relative risks. This combining step is based on the assumption that dementia is a relatively rare event and that the three different measures are therefore valid estimates of relative risk (17), and that it has been used previously (18).

The data points for the meta-analysis of binary outcomes were the logarithms of the relative risks and their standard errors. The standard errors of the relative risks are typically estimated from the 95 percent confidence interval of the log relative risk by dividing the width of the interval by 3.92 (which is twice the 97.5th percentile of the standard normal distribution). Studies that examined three smoking statuses (current, former, and never) provided data for only current-versus-never and former-versus-never comparisons. Thus, conservative estimates for the current-versus-former comparison were mathematically derived from results reported for current versus never and former versus never. For continuous outcomes, the effect size was defined as the mean difference in rate of change in the outcome between two groups, typically represented by the linear regression coefficient (ß) of the smoking variable after adjusting for other covariates.

Heterogeneity among studies was examined by using standard {chi}2 tests (19). To improve sensitivity of detecting heterogeneity among studies, a p value of 10 percent was used (19). Fixed-effect meta-analysis (inverse variance method) was utilized to pool estimates if there was no evidence of heterogeneity. If heterogeneity was present, the DerSimonian and Laird random-effects method was used to pool effect sizes (20, 21). Both types of pooled effect are weighted such that the weight is inversely proportional to the standard error of the estimate of each study. Therefore, sample size is accounted for in the pooled effects since typically larger studies produce estimates with lower standard errors (higher precision) and hence are given larger weight.

The small number of studies (range, 2–5) within each group of studies with compatible measures precluded investigation of heterogeneity via meta-regression, subgroup analysis, or assessment of publication bias.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Of 6,455 abstracts identified in the database search, data were available for 30 reports from prospective cohort studies. Only 19 reports included data suitable for inclusion in meta-analyses (7, 9–16, 22–31). Consequently, 11 studies with data, or for which data were supplied by authors, could not be included in the meta-analysis because of a lack of compatibility with any other study (5, 32–41). Figure 1 shows the stages in identifying studies for inclusion in our review. No relevant clinical trials meeting study criteria were identified. Characteristics of the 19 studies included in meta-analyses are shown in table 2.


Figure 1
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  		FIGURE 1. Process for identifying studies for inclusion in the review. WHICAP, Washington Heights Inwood Columbia Aging Project.

 

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  		TABLE 2. Characteristics of studies included in the review of smoking as a risk factor for dementia and cognitive decline

 
A total of 13,786 participants were included in the 10 studies on smoking and Alzheimer's disease. Length of follow-up ranged from 2 to 30 years. A total of 4,888 participants from two studies were included in analyses of smoking and vascular dementia. A total of 3,767 participants from five studies were included in analyses of smoking and any dementia. Although the Atherosclerosis Risk in Communities study (37) reported cognitive performance at follow-up, it could not be included in the meta-analysis because of the lack of compatible studies with which results from this study could be pooled. Therefore, the outcome of cognitive performance at follow-up was not included in the meta-analyses. Regarding the other cognitive outcomes, there were three compatible studies including 7,872 participants for cognitive performance change, three compatible studies including 766 participants for cognitive decline, and three compatible studies including 8,385 participants for cognitive impairment.

Current smokers versus never smokers
The relative risk estimates from the individual studies and the pooled estimates for current smokers versus nonsmokers regarding the dementia outcomes and the effect size for the yearly cognitive change outcome are shown in table 3. Compared with never smoking, current smoking was a significant risk factor for all outcomes analyzed. Compared with never smokers, current smokers had 1.79 times (95 percent CI: 1.43, 2.23) the risk of incident Alzheimer's disease, 1.78 times (95 percent CI: 1.28, 2.47) the risk of incident vascular dementia, and 1.27 times (95 percent CI: 1.02, 1.60) the risk of any dementia. Current smokers also showed a significantly larger yearly decline in Mini-Mental State Examination scores compared with never smokers over the follow-up period (ß = –0.13, 95 percent CI: –0.18, –0.08).


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  		TABLE 3. Relative risks of dementia and cognitive decline for current smokers versus never smokers

 
Ever smokers versus never smokers
The individual study and pooled relative risks for ever smokers versus never smokers for Alzheimer's disease, any dementia, and cognitive impairment are shown in table 4. The pooled results showed that, compared with never smokers, those who reported ever having smoked were not at increased risk of Alzheimer's disease, any dementia, or cognitive impairment.


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  		TABLE 4. Relative risks of dementia and cognitive impairment for ever smokers versus never smokers

 
Former smokers versus never smokers
The individual and pooled relative risks results for former smokers versus never smokers regarding Alzheimer's disease, vascular dementia, and any dementia and the effect size for the yearly cognitive change outcome are shown in table 5. The pooled results indicate that for the dementia outcomes, former smokers were not at increased risk compared with never smokers. There was, however, evidence of a higher rate of cognitive decline for former smokers compared with never smokers (ß = –0.07, 95 percent CI: –0.11, –0.03).


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  		TABLE 5. Relative risks of dementia and cognitive decline for former smokers versus never smokers

 
Current smokers versus former smokers
Individual study and pooled relative risks for current smokers versus former smokers regarding all dementia outcomes and the effect size for the yearly cognitive change outcome are shown in table 6. Compared with former smoking, current smoking was a significant risk factor for Alzheimer's disease (RR = 1.70, 95 percent CI: 1.25, 2.31) but not for vascular dementia (RR = 1.26, 95 percent CI: 0.60, 2.63) or any dementia (RR = 1.30, 95 percent CI: 0.96, 1.77). There was also evidence that, compared with former smokers, current smokers showed a greater yearly cognitive decline in the follow-up period (ß = –0.07, 95 percent CI: –0.13, –0.02).


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  		TABLE 6. Relative risks of dementia and cognitive decline for current smokers versus former smokers

 
Current smokers versus former and never smokers
The individual study and pooled relative risks for current smokers versus former/never smokers regarding Alzheimer's disease and cognitive decline are shown in table 7. Pooled estimates suggested an increased risk for current smokers for cognitive decline (RR = 1.41, 95 percent CI: 1.61, 1.71) but not Alzheimer's disease (RR = 1.25, 95 percent CI: 0.49, 3.17).


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  		TABLE 7. Relative risks of dementia and cognitive decline for current smokers versus formers and never smokers

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
The results of this study clearly show that, when compared with people who have never smoked, current smokers have an increased risk of dementia and cognitive decline ranging from 40 percent to 80 percent, depending on the outcome examined. However, our analyses did not reveal an increased risk of dementia or cognitive decline for ever smoking compared with never smoking. The "ever smoker" category includes current with previous smokers, which complicates interpretation of these results. When former smokers were compared with never smokers, they were not found to have an increased risk of dementia but did show an increased risk of yearly decline in the Mini-Mental State Examination. Compared with former smokers, current smokers had an increased risk of Alzheimer's disease and a yearly decline in the Mini-Mental State Examination, but there was no difference in their risk of vascular dementia or any dementia. Finally, current smokers had an increased risk of cognitive decline compared with "former and never" smokers.

The results of these analyses must be interpreted in the context of the strengths and limitations of the available data. The categories of "former" and "ever" smoker are nonspecific and could equate persons who smoked for a short period very early in life with persons who smoked heavily for decades. The strongest comparisons are clearly between "current" smokers and "never" smokers. Most weight should be placed on the results comparing these groups. The fact that consistent findings occurred in analyses of small numbers of studies implies that stronger results may be observed if more studies were available for inclusion in a meta-analysis. Therefore, the results strongly supported the finding that current smoking is a risk factor for cognitive decline and dementia among older adults.

Former smokers were at significantly lower risk than current smokers of Alzheimer's disease and yearly cognitive decline but were no different from current smokers regarding their risk of vascular dementia and any dementia. Smoking cessation is associated with reduced risk of lung cancer (42), cardiovascular risk (43), and cancer (44). It is therefore possible that the effects of smoking on cognition are not evident in a proportion of former smokers who may have "recovered" from the detrimental effects of smoking on the brain and cognitive function. A reduction in inflammatory markers such as C-reactive protein is evidenced after smoking cessation (45). Similar mechanisms of reduced inflammation or oxidative stress (46) may lead to a reduction in risk of cognitive decline and dementia among former smokers, but further research is required to test this hypothesis and determine the time period after which risk begins to decline. It is also possible that consistent differences between ever smokers and never smokers were not found because the category of ever smoker included such a broad range of possible smoking duration.

The studies selected for this review had baseline samples of subjects aged mostly in their mid-seventies and so the results can be confidently generalized to this age group only. It is likely that smokers in late adulthood have a lifetime history of smoking so that the observed association between current and never smokers reflects the accumulated effect of smoking over decades. There were insufficient data to evaluate the relation between duration of smoking and dementia risk. Too few studies reported data on pack-years to enable analysis of this relation.

The present review was limited by the small number of comparable studies in any one category, such that we were unable to investigate sources of heterogeneity or test for publication bias. The fact that seven studies did not focus on smoking but reported results incidentally (11, 15, 23, 25, 26, 28, 29), with data obtained from authors, reduced potential publication bias. It is possible that an initial screening of potentially relevant articles on the basis of title and abstract alone was insufficient to detect the presence of data relevant to dementia or cognitive decline within the body of an article. Manually searching all prospective studies of dementia or cognitive decline for data on smoking exposure would overcome this problem.

Because our review is based on observational studies, it is possible that other health and lifestyle factors associated with smoking explain the associations between smoking and dementia and smoking and cognitive decline. For example, smokers may have poorer nutrition, have poorer general health, be more likely to drink harmful levels of alcohol, or undertake less physical activity. Although many studies adjusted for demographic and health factors that may influence the observed associations, there was inconsistency among studies in the choice of covariates.

Smoking may also affect dementia risk via its effect on other medical conditions such as coronary events (47), and it may interact with other cardiovascular risk factors in a synergistic or additive manner (7). It may also interact with genetic factors such as apolipoprotein E genotype (APOE) to increase the risk of dementia (48). Two studies included in our review reported data on APOE as a covariate (7, 15), but neither reported interactions between smoking and APOE genotype specifically. However, a report from the Rotterdam Study found that APOE {epsilon}4 carriers who were smokers had no increased risk of dementia, whereas APOE {epsilon}4 noncarriers who were smokers had double the risk of dementia and Alzheimer's disease (49).

The strengths of this review include its strict selection criteria, ensuring that only high-quality studies were included; inclusion of publications in which smoking was not the main variable of interest to counteract publication bias; and the fact that a number of studies had large sample sizes and long follow-ups.

We conclude that elderly current smokers are at increased risk of dementia and cognitive decline compared with those who have never smoked but that there remains insufficient data to determine how past smoking affects risk of both cognitive decline and dementia. Cognitive outcomes should be measured in clinical trials of smoking cessation. Public health information about smoking should include warnings that it may increase the risk of dementia.


   ACKNOWLEDGMENTS
 
The National Health and Medical Research Council of Australia funded this research.

The authors thank Lee-Fay Low for checking coding of some of the data. They also thank the authors who kindly provided data for the meta-analyses.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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