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What this paper adds
Environmental tobacco smoke (ETS) increases the risks of cancer, and respiratory and cardiovascular diseases, but its association with dementia remains unclear.
No study has previously investigated the dose–response relationship between ETS and dementia syndromes.
The risk of severe dementia syndromes was dose-dependently increased with ETS exposure.
The effect was similar between never smokers and smokers, and was predominately due to ETS exposure at work.
ETS should be considered an important risk factor for severe dementia syndromes.
Dementia syndromes are comprehensive chronic mental disorders, the main clinical features being cognitive decline and varying degrees of personality change. They comprise Alzheimer's disease, vascular dementia and other rarer conditions. Dementia syndromes are relatively common, increasing in prevalence, and the largest cause of disability, particularly disability that affects self-care and the ability to carry out domestic tasks.1 They are one of the world's biggest health problems and a major public health challenge that is increasing as populations age.2
Previous studies have shown that cigarette smoking substantially increases the risk of Alzheimer's disease and all types of dementia.3 ,4 This has stimulated speculation that environmental tobacco smoke (ETS), also known as second-hand smoke or passive smoking, may also have a role. In a recent study, Llewellyn et al5 reported a significant association between ETS and cognitive impairment (defined by the lowest 10% of scores on a battery of neuropsychological tests) in a UK population aged ≥50. In Italy, Orsitto et al6 observed that both mild cognitive impairment and dementia were related to ETS in 856 patients aged ≥65 who were consecutively admitted to a geriatric unit. In the USA, however, Barnes et al7 did not find a significant relationship between ETS and risk of dementia in a cohort of 970 older people. The uncertain association between ETS exposure and risk of dementia is compounded by lack of data, urging further investigation. In this study, we examine the dose–response relationship between ETS exposure and dementia syndromes (as opposed to dementia cases).
The four-province study
The methods employed in the four-province study have been fully described before.8 In brief, in 2008–2009, following our previous studies in Anhui province,10 ,11 we chose one urban and one rural community from each of four provinces (Guangdong, Heilongjiang, Shanghai and Shanxi) as the study fields and sought to recruit 500 or more participants from each community. We employed a cluster random sampling method to select residential communities from each of the four provinces (detailed location data are available on request). The target population consisted of residents aged ≤60 years who had lived in the area for at least 5 years. Ethics approval for the study was obtained from the Research Ethics Committee, University College London, UK, and the local governments in China. Based on the residency lists of the district and village committees, we recruited a total of 4314 participants, with an overall response rate of 93.8%. Permission for interview and informed consent were obtained from each participant or, if that was not possible, from the closest responsible adult. The participants were interviewed at home by each local survey team from Guangzhou, Harbing and Shanxi Medical Universities, and the School of Public Health of Fudan University. Two researchers from each team were trained at Anhui Medical University, where we had completed several surveys of mental illness in older people and had a skilled and experienced interview team.9–11 Researchers then returned to their own centres, passed on their skills to local research teams and re-trained the interviewers. The main interview materials were a general health and risk factors questionnaire9 and the Geriatric Mental State Examination (GMS)—a comprehensive semi-structured mental state interview.8 ,12 According to standard procedures,13 ,14 we measured systolic and diastolic blood pressure, and weight and waist circumference in all participants.
The third wave survey of the Anhui study
The methods employed in the different wave surveys of the Anhui study have been described previously.8 ,9 In brief, in 2001–2003 we examined a random sample of 3336 men and women aged ≤60 years in urban and rural Anhui, China (wave 1) using the standard GMS method.12 After completing the wave 2 interview in the year following the baseline investigation,15 we carried out the third wave survey during 2007–2009 and successfully re-interviewed 1757 participants, obtaining a response rate of 82.4% of surviving cohort members.9 The third wave interview protocol was similar to that in the four-province study mentioned above, and was described in a previous publication.9
Assessment of dementia syndromes
A computer program-assisted diagnosis system, the Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT),12 was used to analyse the information from the GMS to identify the principal mental disorders in the study participants. AGECAT was developed using a theoretical model and tested on sample populations diagnosed by psychiatrists. It first attempts to replicate the process by which a psychiatrist diagnoses a syndrome, and then offers a differential diagnosis. GMS symptoms are combined into 150 ‘symptom components’. In stage I, the symptom components are assembled into groups that characterise the major symptoms of each syndrome. The scores on these individual groups determine the confidence of the diagnosis of the syndrome level. Thus the system uses both quantitative and qualitative measures to determine levels of confidence and utilises numerous clinical decisions to allocate symptom components to syndrome levels. Levels of confidence of diagnosis (0–5) for individual participants are assigned for each of the eight diagnostic syndromes: organic disorder, depression, mania, schizophrenia and paranoia, obsession, phobia, hypochondria, and general anxiety.16 In stage II the various syndrome levels are compared with each other to derive a final differential diagnosis and a level of confidence of diagnosis (0–5). A level of ≥3 in most circumstances designates a ‘case level’, which corresponds with what psychiatrists usually recognise as ‘a case for intervention’ for organic mental disorder. The GMS-AGECAT diagnosis has been validated in a variety of populations,12 including older Chinese populations.12 ,17
Definition of ETS exposure
We asked the participants for information on smoking habits and ETS exposures, using a questionnaire similar to that employed in the Scottish MONICA surveys.18 ,19 Current smokers were those who gave a positive answer to the question ‘Do you smoke cigarettes now?’ and provided additional information including the number of cigarettes smoked each day, the maximum number smoked each day in the last 2 years, and the duration of the smoking habit. If not currently smoking, participants were asked about their smoking history and related information. We defined ‘never smokers’ as those who gave negative answers to both enquiries. After giving details of smoking status, all participants were required to provide the answers ‘yes’ or ‘no’ relating to exposure to ETS. Three sources of ETS exposure were given; home, workplace, and other places, and respondents were given three choices: no, none at all; yes, some; or yes, a lot. All participants were asked how many years they were exposed to each of three sources of ETS.
The four-province data were combined with the Anhui wave 3 data for analysis (waves 1 and 2 did not have ETS data available). Of 6071 participants, 5962 reported smoking status, of whom 5928 had data on ETS exposure available. Exclusion of seven participants who did not have GMS-AGECAT data, left 5921 for analysis in this study. We defined levels 1–2 organic disorder syndromes as moderate dementia syndromes and levels 3–5 as severe syndromes.16 ,20 We employed a Cox regression model used previously21 ,22 to calculate the RR of increased dementia syndromes among participants with ETS compared to those without. Moderate and severe syndromes were compared individually to each of the other syndromes. In the analysis we adjusted for age, sex, smoking status, urban/rural location, educational level, occupational class, annual income, marital status, religion, current drinking, visiting children or relatives, hypertension, stroke and depressive syndromes, and accounted for the clustering effect of the five-province geographical area in the model. We further investigated the RR for different sources of ETS exposure (at home, at work and in other locations) and their durations in relation to the excess of dementia syndromes. We scored the three exposure levels (‘No, none at all’, ‘Yes, some’ and ‘Yes, a lot’) as 0, 1 and 2, respectively, and calculated cumulative exposures by multiplying each score by exposure duration. We included cumulative exposure in the analysis. All analyses were performed in Stata V.11 (StataCorp, College Station, Texas, USA).
Of 5921 participants, 2153 (36.4%) were exposed to ETS (1159 (30.8%) of 3769 never smokers, and 994 (46.2%) of 2152 former/current smokers) (table 1). In comparison to those without ETS exposure, ETS-exposed participants were significantly younger, and more likely to have smoked, live in a rural area, have lower education and occupational class, be married (versus widowed), have a religious belief, drink alcohol and visit children (table 1). There were no significant differences between exposed and non-exposed groups regarding body mass index, annual income, hypertension, diabetes, stroke and depressive syndrome. However, participants exposed to ETS had a significantly increased risk of dementia syndromes (table 1).
The age-sex adjusted analysis accounting for the clustering effect of the five-province geographical data showed a significantly increased relative risk for severe dementia syndromes (1.61, 95% CI 1.30 to 1.98; p<0.001) but not for moderate syndromes (1.14, 95% CI 0.89 to 1.45; p=0.305). After further adjustment for smoking status, urban/rural location, educational level, occupation, income, marital status, religion, current drinking, visiting children or relatives, hypertension, stroke and depressive syndrome, the RR was 1.29 (95% CI 1.05 to 1.59; p=0.014) and 0.96 (95% CI 0.84 to 1.09; p=0.502), respectively. The corresponding figures for the four-province study were 1.33 (95% CI 0.98 to 1.81) and 1.08 (95% CI 0.94 to 1.24), and for the Anhui third wave survey 1.29 (95% CI 0.99 to 1.68) and 0.97 (95% CI 0.78 to 1.22).
Separate data analysis for never smokers and former/current smokers showed similar results: an increased risk of severe syndromes of 1.33 (95% CI 1.01 to 1.74) in never smokers and 1.23 (95% CI 1.02 to 1.49) in former/current smokers, with corresponding figures for moderate syndromes of 1.06 (95% CI 0.78 to 1.45) and 0.81 (95% CI 0.57 to 1.17), respectively.
Table 2 shows the numbers and percentages of participants with dementia syndromes in relation to different sources of ETS, exposure duration and cumulative exposure. The dementia syndromes were significantly related to ETS exposure across different sources, exposure duration and cumulative exposure. It appears that the more severe the syndrome, the stronger the association with ETS.
Table 3 shows the RR of severe syndromes in relation to different sources of ETS and cumulative exposures. The increased RR for all participants was consistent across different sources of exposure. The risk was significantly increased with duration of exposure at home, at work and in other locations, and with cumulative dose. A pattern of slightly increased RRs was seen in never smokers (table 3). Significant associations were also found in former/current smokers. However, the data for moderate syndromes showed no such relationships (data available on request).
In this large population-based study of dementia in China, we observed a significant increase in the risk of severe dementia syndromes among participants exposed to ETS. The impact of ETS was dose-dependent, and significantly affected both never smokers and former/current smokers.
China is the largest producer and consumer of tobacco in the world: 30% of the world's cigarettes are consumed by China's 350 million smokers.23 A 1996 national survey showed that the prevalence rate for ever smokers was 66.9% for men and 4.2% for women over the age of 15 years, and that 53.5% of non-smokers were regularly exposed to ETS.23 In 2002, ever-smoking rates in males and females aged 15 and over were 66.0% and 3.1%, respectively, and the prevalence of ETS in non-smokers was 51.9%.24 Since the World Health Organization Framework Convention on Tobacco Control (FCTC) came into force in January 2006, the Chinese government has actively promoted the introduction of smoke-free environments in hospitals, in schools, on public transportation and in other public places.25 However, the implementation of such policies, and their impact, has been far from satisfactory. Recent data show that the prevalence of ETS among never smokers has not reduced significantly, with 52.5% exposed to ETS daily.26 ETS exposure has many detrimental effects on the cardiovascular system, including increased coagulability of blood platelets, endothelial dysfunction, decreased coronary flow velocity reserves and accelerated atheroma genesis.27 Moreover, endothelial dysfunction may be related to reduced clearance of β-amyloid protein, which is considered to be implicated in the pathogenesis of Alzheimer's disease.28 Thus it is not surprising that exposure to ETS was found to increase the risk of dementia syndromes in this study.
In the current study, definitions of dementia syndromes were based on symptoms reflecting cognitive impairment consistent with a diagnosis of dementia.12 A score of ≥3 on the GMS-AGECAT indicates an ‘organic state’ which may also include acute confusional states. The large number of studies which have used GMS-AGECAT29 indicate that acute confusional states are common in hospital-based practice. However, the probable rate of 0.5–1% in the community is small enough to be ignored in most studies of dementia; usually such individuals die or recover and are consequently not included in analysis in multiphase epidemiological studies of dementia. In the Chinese community, severe dementia syndromes diagnosed by the GMS-AGECAT predicted the risk of dementia being diagnosed by psychiatrists. In the Anhui cohort which was followed up over 7.5 years,9 those with baseline severe dementia syndromes had an increased risk of incident dementia; after adjusting for age, sex, annual income and hypertensive status, the hazards ratio was 2.36 (95% CI 1.02 to 5.47). In the earlier data analysis of women in the four-province study, we observed that ETS exposure was also significantly associated with severe dementia diagnosed by the GMS-AGECAT.30
Strengths and weaknesses of the study
The main contribution of this study is that it provides information on the dose–response relationship between ETS exposure and severe dementia syndromes. China has had high levels of both active and passive smoking,23 ,31 and also has the highest number of dementia sufferers in the world,2 with increasing rates of dementia in the future suggested,16 allowing the association between ETS exposure and dementia syndromes to be examined. A second strength is that we included a relatively large number of study participants and the response rate was high. Although the nature of the study and response rate in the third wave survey in Anhui differed from those in the four-province study, separate data analysis of results from the four-province study and the Anhui study demonstrated similar findings. In addition to increasing study power, inclusion of the Anhui study data in the analysis allowed us to investigate whether the onset of dementia rendered participants more liable to ETS exposure (reverse causality). Of 1694 participants examined in this study, 116 had severe dementia syndromes at baseline, 219 had moderate syndromes and 1359 did not have dementia, and their prevalences of ETS exposure at wave 3 were 30.2%, 35.2% and 31.0%, respectively (p=0.444). The findings showed no association between baseline dementia syndromes at wave 1 and follow-up ETS exposure at wave 3. A third strength is that we adjusted for 14 important variables, minimising the residual effect of confounding. In addition to accounting for the geographical clustering effect in analysis, we directly calculated the RR of dementia syndromes in relation to ETS, avoiding its conversion from the OR.32 We did not use a logistic regression model as it is likely to overestimate the association when the outcome prevalence is common (>10%).
Our study has several limitations. First, the study was cross-sectional and the causal relationship found between ETS exposure and severe dementia syndromes needs to be confirmed by longitudinal follow-up studies. However, it is unlikely that the data on ETS status were affected by differential reporting bias in non-dementia versus dementia cases as ETS was determined before a diagnosis was established. Most Chinese people are unaware of the potential relationship between dementia and ETS exposure. Thus, bias resulting from over-reporting of exposure in patients with dementia syndromes and their carers was unlikely. Furthermore, we have excluded the possibility of reverse causality with ETS exposure resulting from the onset of dementia syndromes in the Anhui cohort data. Second, we did not measure cotinine level to quantify ETS exposure, which is a major limitation. Self-reported ETS may underestimate exposure,33 although previous research has indicated that it satisfactorily differentiates between relative levels of exposure.34 Our previous studies18 ,19 suggest the combination of the questionnaire and cotinine level measurement increases the statistical power. Thus the association between ETS and dementia symptoms as found in this study may be a conservative estimate.
In conclusion, as far as we know, our study is the first to investigate the relationship between ETS exposure and dementia syndromes. A significant association between ETS exposure and severe dementia syndromes was found. The relationship is dose-independent, and ETS significantly affects never smokers and former/current smokers. The similarity of effects of ETS in smokers and never smokers is consistent with findings in a population-based study in the UK,5 suggesting that ETS exposure is a strong risk factor for severe dementia syndromes in the general population. The findings from this study, while needing confirmation from prospective longitudinal research, strengthen the case for public health measures to protect people from exposure to ETS. The increased risk of severe dementia in those exposed to ETS is similar to increased risk of coronary heart disease,35 suggesting that urgent preventive measures should be taken. At present 93% of the world's population live in countries not fully covered by smoke-free public health regulations.36 More campaigns against ETS exposure and tobacco use in the general population will help decrease the risk of severe dementia and reduce the dementia epidemic worldwide.
The authors thank the participants and all who were involved in the surveys in the Anhui cohort study and the four-province study.
Contributors RC: study concept and design; ZH, YM, XQ and RC: data collection and supervision; DZ, KW, YC, MH, ZH and RC: analysis and interpretation of data; RC, KW, YC and JRC: drafting of the manuscript; DZ, XQ, MH, ZH and YM: critical revision of the manuscript for important intellectual content; RC, KW and ZH: obtaining funding; DZ, ZH, RC and YM: administrative, technical and material support. RC has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by research grants from the Alzheimer's Research Trust and BUPA Foundation, UK. Dr Dongmei Zhang was funded by the University of Wolverhampton Strategic Research Development Fund. The sponsors of the study had no role in study design, data analysis, data interpretation or writing of the report. The opinions expressed in this report are not necessarily those of the funders.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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