Abstract
Background
the relations of cigarette smoking and alcohol drinking with risk of cognitive impairment remain inconsistent.
Methods
to examine the independent and joint relations of smoking and alcohol drinking with cognitive impairment, we used data from 16,948 men and women, who had been followed-up for 16–23 (mean of 20) years as participants of the Singapore Chinese Health Study, a population-based prospective cohort. Data on smoking and alcohol drinking were collected at baseline (1993–98), when participants were aged 45–74 (mean 53) years. Cognition was assessed using a 30-item Mini-Mental State Examination during follow-up three visits (2014–16), when participants were aged 61–96 (mean 73) years. Multivariable logistic regression models were used to estimate the odd ratios (ORs) and 95% confidence intervals (CIs).
Results
cognitive impairment was present in 2,443 (14.4%) participants. Compared with non-current smokers, current smokers had 20% increased risk (OR = 1.20, 95% CI = 1.04–1.39). Compared with those who drank less than weekly, regular alcohol drinking (at least weekly) had 17% increased risk (OR = 1.17, 95% CI = 1.01–1.36). Compared with those who were neither smokers nor drinkers, those who were either current smokers or regular drinkers alone had no significantly increased risk, while the risk was highest in those who were both current smokers and regular drinkers (OR = 1.77, 95% CI = 1.39–2.26, Pinteraction = 0.003).
Conclusions
co-existence of smoking and regular alcohol drinking at midlife had a much stronger impact than the individual factors on risk of cognitive impairment in late life.
Keywords: smoking, alcohol drinking, cognition, epidemiological study, Chinese, older people
Introduction
As a possible early sign of dementia, cognitive impairment not only affects functional activities of daily living and quality of life, but also increases the risk of premature death in later life [1, 2]. Without effective therapies to reverse cognitive impairment, coupled with the expectant rise in global rates of cognitive impairment and dementia due to ageing, there is an urgency to identify modifiable risk factors of cognitive impairment to prevent dementia and preserve quality of life among older people.
Smoking and alcohol drinking are two common and correlated lifestyle factors [3, 4]. Smoking has been recognized as a risk factor for cognitive impairment in prospective studies [5–7], and is responsible for about 5% of dementia at the population level [8]. Heavy alcohol drinking is a risk factor for cognitive impairment [9], but the association with moderate drinking remains controversial. Although some cohort studies concluded that moderate alcohol drinking might reduce risk of cognitive decline and dementia [10, 11], other studies reported that even moderate level of alcohol might be detrimental to brain health and cognitive performance [12–14]. Two prospective studies suggested that co-existence of smoking and alcohol drinking could have a much stronger risk of cognitive decline or dementia than the individual factors [15, 16], while another prospective study showed that smoking might neutralize the possible benefits of moderate drinking [17].
Therefore, in this study, we investigated the independent and combined relations of smoking and alcohol consumption with risk of cognitive impairment using data from the Singapore Chinese Health Study, a population-based cohort of middle-aged and older Chinese people in Singapore that has been followed-up for two decades.
Methods
Study population
The Singapore Chinese Health Study is a cohort of 63,275 individuals of Chinese ethnicity aged 45–74 years old recruited from permanent residents or citizens of Singapore living in government-built housing estates, where 86% of Singapore residents resided during the time of recruitment from 1993 to 1998. Detailed information about the study has been reported previously [18].
At baseline, each participant was interviewed in-person using a structured questionnaire to acquire information including education, cigarette smoking, alcohol drinking, height, weight, physical activity, habitual diet and medical history. After the baseline interview, participants were re-contacted for follow-up 1 (1999–2004), follow-up 2 (2006–10) and follow-up 3 (2014–16) interviews. Ethics approval was obtained from the Institutional Review Board of the National University of Singapore. All participants gave written informed consent.
Exposure variables
Cigarette smoking was assessed using the question: ‘Have you ever smoked at least one cigarette a day for one year or longer’. Three options were provided: ‘no’ (never smokers), ‘yes, but I quit smoking’ (former smokers) and ‘yes and I currently smoke’ (current smokers). Smokers were further asked to report age at starting or quitting smoking, the average number of cigarettes smoked per day, and the number of years smoked.
Habitual diet in the past year was measured using a validated 165-item food frequency questionnaire [18]. Two dietary patterns were derived: ‘vegetable–fruit–soy’ and ‘meat-dim-sum’ patterns, which were associated with risks of diabetes and cardiovascular mortality in this population [19, 20]. For alcohol drinking, participants were asked in separate questions about their consumption of beer, wine, western hard liquor and Chinese hard liquor, and to choose from eight categories of frequency (ranging from ‘never or hardly ever’ to ‘2 or more times a day’) and four defined portion sizes.
Outcome variables
Cognitive performance was evaluated only once during face-to-face interviews at the follow-up three visits using a Singapore modified version of the Mini-Mental State Examination (MMSE) [21]. All interviewers were systematically trained by an experienced geriatric epidemiologist (L. Feng), and 20% of the interview recordings were randomly selected for quality control. The interviewers were re-trained and re-assessed if they did not follow the protocol. The 30-item MMSE includes orientation, attention, immediate and delayed recall, language and simple ability to follow verbal and written instructions [22]. Previous studies have shown that education levels significantly affected the MMSE score [23, 24]. Thus, we used education-specific cut-off points defined in the Shanghai Dementia Survey, because their participants had comparable education levels with our participants [24]. The cut-off points were 17/18 for those with no formal education, 20/21 for those with primary school education, and 24/25 for those with secondary school or higher education.
A total of 17,107 surviving participants aged 61–96 years completed MMSE test between July 2014 and February 2016. We excluded participants with missing value on cognitive tests (n = 55), and participants who were mute (n = 1), blind (n = 55), or deaf (n = 48), leaving 16,948 participants (6914 men and 10,034 women) for the final analysis.
Statistical analysis
Multivariate logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for independent and combined relations of cigarette smoking and alcohol consumption with cognitive impairment. Covariates included age at MMSE measurement (year), year of recruitment (1993–95, 1996–98), sex, dialect group (Hokkien, Cantonese), marital status (married, separated/divorced, widowed, never married), education level (no formal education, primary school, secondary school or above), tea intake (none, monthly, weekly, daily), coffee intake (none/less than daily, 1 cup/day, ≥2 cups/day), physical activity (hours per week spent on moderate activities, strenuous sports and vigorous work: none, 0.5–3.9 h/week, ≥4.0 h/week), total energy intake (kcal/day), body mass index (< 18.5, 18.5–22.9, 23–27.4, ≥27.5 kg/m2), dietary scores for the vegetable–fruit–soy dietary pattern and meat-dim-sum dietary pattern (quartiles), history of physician-diagnosed hypertension, diabetes, cardiovascular disease and cancer.
We also conducted sensitivity analysis by excluding those with history of cardiovascular disease or cancer at baseline, or adjusting for age at baseline instead of age at MMSE measurement. In addition, we used generalized linear models to compare adjusted mean MMSE scores by smoking and alcohol drinking. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). Statistical significance was defined as two-sided P values <0.05.
Results
The mean age at MMSE measurement was 73.2 years, and 40.8% were men. The majority (77.8%) of them had never smoked, 9.1% were former smokers and 13.1% were current smokers. The majority (88.5%) drank alcohol less than weekly, while 8.7% drank weekly and 2.8% drank daily (Table 1). Compared with never smokers or with those drinking less than weekly, current smokers or weekly/daily drinkers were more likely to be men, older and married and to drink coffee or tea daily (Table 1). Additionally, the prevalence of current smoking was 11.0% among those who drank alcohol less than weekly, 24.8% among weekly drinkers and 43.0% among daily drinkers.
Table 1.
Characteristics of study participants according to cigarette smoking and alcohol drinking status
| Variables | Number of participants | Smoking status | Drinking frequency | ||||
|---|---|---|---|---|---|---|---|
| Never | Former | Current | <Weekly | Weekly | Daily | ||
| Number of participants | 16948 | 13186 | 1549 | 2213 | 15002 | 1479 | 467 |
| Age at baseline, mean (SD), y | 53.0 (6.2) | 52.7 (6.2) | 55.0 (6.8) | 53.3 (5.9) | 53.1 (6.3) | 52.5 (6.0) | 53.2 (5.9) |
| Age at MMSE testing, mean (SD), y | 73.2 (6.4) | 72.9 (6.4) | 74.9 (6.9) | 73.6 (6.1) | 73.3 (6.4) | 72.4 (6.1) | 73.4 (6.0) |
| Men (%) | 6914 (40.8) | 3596 (27.3) | 1404 (90.6) | 1914 (86.5) | 5448 (36.3) | 1104 (74.6) | 362 (77.5) |
| Married (%) | 15016 (88.6) | 11586 (87.9) | 1447 (93.4) | 1983 (89.6) | 13225 (88.2) | 1357 (91.8) | 434 (92.9) |
| Hokkiens (%) | 8503 (50.2) | 6463 (49.0) | 736 (47.5) | 1304 (58.9) | 7578 (50.5) | 663 (44.8) | 262 (56.1) |
| Education level (%) | |||||||
| No formal education | 3193 (18.8) | 2744 (20.8) | 134 (8.6) | 315 (14.2) | 2987 (19.9) | 144 (9.7) | 62 (13.3) |
| Primary school | 7587 (44.8) | 5569 (42.2) | 827 (53.4) | 1191 (53.8) | 6619 (44.1) | 711 (48.1) | 257 (55.0) |
| Secondary school or higher | 6168 (36.4) | 4873 (37.0) | 588 (38.0) | 707 (32.0) | 5396 (36.0) | 624 (42.2) | 148 (31.7) |
| Tea intake (%) | |||||||
| None | 6464 (38.1) | 5190 (39.4) | 485 (31.3) | 789 (35.7) | 5854 (39.0) | 437 (29.6) | 173 (37.0) |
| Monthly | 2073 (12.2) | 1607 (12.2) | 171 (11.0) | 295 (13.3) | 1852 (12.4) | 166 (11.2) | 55 (11.8) |
| Weekly | 4435 (26.2) | 3488 (26.4) | 430 (27.8) | 517 (23.4) | 3878 (25.8) | 445 (30.1) | 112 (24.0) |
| Daily | 3976 (23.5) | 2901 (22.0) | 463 (29.9) | 612 (27.6) | 3418 (22.8) | 431 (29.1) | 127 (27.2) |
| Coffee intake (%) | |||||||
| None/less than daily | 5165 (30.5) | 4367 (33.1) | 440 (28.4) | 358 (16.2) | 4728 (31.5) | 346 (23.4) | 91 (19.5) |
| 1 cup/day | 6159 (36.3) | 5007 (38.0) | 501 (32.3) | 651 (29.4) | 5473 (36.5) | 502 (33.9) | 184 (39.4) |
| ≥2 cup/day | 5624 (33.2) | 3812 (28.9) | 608 (39.3) | 1204 (54.4) | 4801 (32.0) | 631 (42.7) | 192 (41.1) |
| Physical activity (%) | |||||||
| None | 10718 (63.3) | 8506 (64.5) | 841 (54.3) | 1371 (61.9) | 9653 (64.3) | 786 (53.1) | 279 (59.7) |
| 0.5–3.9 h/week | 3954 (23.3) | 3058 (23.2) | 434 (28.0) | 462 (20.9) | 3414 (22.8) | 437 (29.6) | 103 (22.1) |
| ≥4 h/week | 2276 (13.4) | 1622 (12.3) | 274 (17.7) | 380 (17.2) | 1935 (12.9) | 256 (17.3) | 85 (18.2) |
| Body mass index, mean (SD), kg/m2 | 23.1 (3.2) | 23.2 (3.2) | 23.5 (3.3) | 22.6 (3.2) | 23.2 (3.2) | 23.1 (3.1) | 22.4 (3.1) |
| Baseline hypertension (%) | 3285 (19.4) | 2609 (19.8) | 396 (25.6) | 280 (12.7) | 3004 (20.0) | 226 (15.3) | 55 (11.8) |
| Baseline diabetes (%) | 828 (4.9) | 623 (4.7) | 116 (7.5) | 89 (4.0) | 757 (5.1) | 54 (3.7) | 17 (3.6) |
| Baseline cardiovascular disease (%) | 422 (2.5) | 288 (2.2) | 88 (5.7) | 46 (2.1) | 385 (2.6) | 34 (2.3) | 3 (0.6) |
| Baseline cancer (%) | 321 (1.9) | 270 (2.1) | 31 (2.0) | 20 (0.9) | 304 (2.0) | 15 (1.0) | 2 (0.4) |
Abbreviations: SD, standard deviation.
The mean MMSE score was 24.8 (SD 3.9), and 2,243 participants (14.4%) had cognitive impairment. Compared with never smokers, the risk of cognitive impairment was increased in current smokers but not in former smokers (Table 2). The OR (95% CI) was 1.20 (1.04–1.39) comparing current smoking with non-current smoking (never and former smoking). Among current smokers, the risk of cognitive impairment increased in a dose-dependent manner with younger age at starting to smoke (Ptrend = 0.04), and with increasing duration of smoking (Ptrend = 0.03), but was not associated with the number of cigarettes smoked per day (Table 2). Compared with those who drank less than weekly, those who drank at least weekly had a 17% increased risk of cognitive impairment (1.17, 1.01–1.36), and the risk increased in a stepwise manner with frequency of drinking (Ptrend = 0.03; Table 2).
Table 2.
Relations of cigarette smoking and alcohol drinking with risk of cognitive impairment
| Risk factors | Number of participants | Number with cognitive impairment | Model 1a | Model 2b | Model 3c |
|---|---|---|---|---|---|
| OR (95% CI) | OR (95% CI) | OR (95% CI) | |||
| Cigarette smoking | |||||
| Never smokers | 13186 | 1874 | 1.00 | 1.00 | 1.00 |
| Former smokers | 1549 | 236 | 1.02 (0.86–1.20) | 0.99 (0.83–1.17) | 0.98 (0.82–1.16) |
| Current smokers | 2213 | 333 | 1.23 (1.07–1.43) | 1.19 (1.02–1.38) | 1.19 (1.03–1.39) |
| Ptrendd | 0.01 | 0.04 | 0.04 | ||
| Non-current smokers | 14735 | 2110 | 1.00 | 1.00 | 1.00 |
| Current smokers | 2213 | 333 | 1.23 (1.07–1.42) | 1.19 (1.03–1.38) | 1.20 (1.04–1.39) |
| Age at starting to smoke cigarettes among current smokers | |||||
| Never smokers | 13186 | 1874 | 1.00 | 1.00 | 1.00 |
| ≥20 | 967 | 156 | 1.21 (1.00–1.48) | 1.17 (0.96–1.42) | 1.18 (0.96–1.44) |
| 15–19 | 862 | 119 | 1.23 (0.99–1.54) | 1.17 (0.94–1.46) | 1.18 (0.94–1.48) |
| < 15 | 384 | 58 | 1.26 (0.93–1.70) | 1.22 (0.90–1.66) | 1.23 (0.91–1.68) |
| Ptrendd | 0.01 | 0.05 | 0.04 | ||
| Number of cigarettes/day among current smokers | |||||
| Never smokers | 13186 | 1874 | 1.00 | 1.00 | 1.00 |
| ≤12 | 877 | 156 | 1.29 (1.06–1.57) | 1.27 (1.04–1.55) | 1.28 (1.05–1.56) |
| 13–22 | 905 | 125 | 1.21 (0.98–1.50) | 1.15 (0.93–1.43) | 1.16 (0.93–1.44) |
| ≥23 | 431 | 52 | 1.09 (0.80–1.50) | 1.00 (0.73–1.37) | 1.01 (0.73–1.38) |
| Ptrendd | 0.05 | 0.23 | 0.20 | ||
| Years of cigarette smoking among current smokers | |||||
| Never smokers | 13186 | 1874 | 1.00 | 1.00 | 1.00 |
| ≤19 | 109 | 15 | 1.24 (0.70–2.20) | 1.17 (0.66–2.08) | 1.18 (0.66–2.10) |
| 20–39 | 1532 | 194 | 1.24 (1.03–1.48) | 1.17 (0.98–1.40) | 1.17 (0.98–1.41) |
| ≥40 | 572 | 124 | 1.21 (0.97–1.52) | 1.19 (0.95–1.50) | 1.21 (0.96–1.52) |
| Ptrendd | 0.01 | 0.04 | 0.03 | ||
| Alcohol drinking | |||||
| Less than weekly | 15002 | 2161 | 1.00 | 1.00 | 1.00 |
| Weekly | 1479 | 208 | 1.16 (0.99–1.37) | 1.15 (0.97–1.35) | 1.15 (0.98–1.36) |
| Daily | 467 | 74 | 1.30 (0.99–1.69) | 1.22 (0.93–1.60) | 1.23 (0.94–1.62) |
| Ptrendd | 0.01 | 0.04 | 0.03 | ||
| Less than weekly | 15002 | 2161 | 1.00 | 1.00 | 1.00 |
| At least weekly | 1946 | 282 | 1.19 (1.03–1.38) | 1.17 (1.01–1.35) | 1.17 (1.01–1.36) |
Abbreviations: CI, confidence interval; OR, odds ratio.
aModel 1: Adjusted for age at MMSE measurement, year of baseline interview, sex, dialect group, marital status and education level.
bModel 2: Model 1 plus smoking status (when analyzing the alcohol-cognition association), drinking status (when analyzing the smoking-cognition association), tea intake, coffee intake, physical activity, body mass index, total energy intake, vegetable–fruit–soy dietary pattern and meat-dim-sum dietary pattern.
cModel 3: Model 2 plus baseline history of hypertension, diabetes, cardiovascular disease and cancer.
dP for linear trend tested by treating factor as continuous variable.
The positive association between current smoking and cognitive impairment was found among those who drank at least weekly (OR = 1.73, 95% CI = 1.27–2.37), but not among those who drank less than weekly (1.08, 0.91–1.27; Pinteraction = 0.003) (Table 3). Expectantly, the positive association between alcohol drinking and cognitive impairment was found among current smokers (1.66, 1.25–2.19), but not among non-current smokers (1.02, 0.85–1.22; Pinteraction = 0.003). In the joint analysis, compared with those who neither smoked currently nor drank alcohol at least weekly, those who either smoked only (1.07, 0.91–1.27) or drank alcohol at least weekly only (1.03, 0.86–1.22) had no significantly increased risk, and the risk was highest in those who both smoked and drank alcohol at least weekly (1.77, 1.39–2.26; Table 3).
Table 3.
Stratified and joint analysis: relations of cigarette smoking and alcohol drinking with risk of cognitive impairment
| Number of participants | Number with cognitive impairment | OR (95% CI)a | Pinteraction | |
|---|---|---|---|---|
| Cigarette smoking | 0.003 | |||
| Drinking less than weekly | ||||
| Non-current smokers | 13357 | 1928 | 1.00 | |
| Current smokers | 1645 | 233 | 1.08 (0.91–1.27) | |
| Drinking at least weekly | ||||
| Non-current smokers | 1378 | 182 | 1.00 | |
| Current smokers | 568 | 100 | 1.73 (1.27–2.37) | |
| Alcohol drinking | 0.003 | |||
| Non-current smokers | ||||
| Drinking less than weekly | 13357 | 1928 | 1.00 | |
| Drinking at least weekly | 1378 | 182 | 1.02 (0.85–1.22) | |
| Current smokers | ||||
| Drinking less than weekly | 1645 | 233 | 1.00 | |
| Drinking at least weekly | 568 | 100 | 1.66 (1.25–2.19) | |
| Cigarette smoking and alcohol drinking | ||||
| Non-current smokers and drinking less than weekly | 13357 | 1928 | 1.00 | |
| Non-current smokers and drinking at least weekly | 1378 | 182 | 1.03 (0.86–1.22) | |
| Current smokers and drinking less than weekly | 1645 | 233 | 1.07 (0.91–1.27) | |
| Current smokers and drinking at least weekly | 568 | 100 | 1.77 (1.39–2.26) |
Abbreviations: CI, confidence interval; OR, odds ratio.
aAdjusted for age at MMSE measurement, year of baseline interview, sex, dialect group, marital status, education level, tea intake, coffee intake, physical activity, body mass index, total energy intake, vegetable–fruit–soy dietary pattern, meat-dim-sum dietary pattern, baseline history of hypertension, diabetes, cardiovascular disease and cancer.
The results remained unchanged after excluding those with history of cardiovascular disease or cancer at baseline (Supplementary Table S1, available in Age and Ageing online), or adjusting for age at baseline instead of age at MMSE measurement (Supplementary Table S2, available in Age and Ageing online). The patterns of the relations of smoking and alcohol drinking with cognitive impairment were similar in the generalized linear models: relative to those who were non-current smokers and drank less than weekly, the mean adjusted MMSE score was significantly lowest in those who were current smokers and drank at least weekly (P < 0.001; Supplementary Table S3, available in Age and Ageing online).
Discussion
In this prospective study of Singapore Chinese, we found that current smoking and weekly/daily alcohol drinking at midlife was associated with an increased risk of cognitive impairment at late life. Individuals with both lifestyle factors experienced the highest risk due to significant interaction between smoking and alcohol drinking.
Our finding of positive association between current smoking and cognitive impairment is concordant with previous studies [5, 7], including those among Chinese populations [25, 26]. A meta-analysis of 19 prospective studies reported that current smokers had greater annual declines in MMSE scores and a 27% increased risk of dementia compared to never smokers [5]. Some previous studies have reported an association between pack-years of smoking (combination of duration and dosage) and cognitive impairment [6, 27], while the association was significant with duration of smoking but not with daily dosage among current smokers in our study. Survival bias is possible in our study given that heavy smokers were more likely to die prematurely and were thus less likely to be involved in the follow-up three visits.
The association between moderate alcohol drinking and cognitive performance remains controversial: some prospective studies in western populations observed better cognitive performance among moderate drinkers [28–30], but other studies with long-term follow-up period (over 20 years) reported opposite results [12–14]. The inconsistency may be due to the lack of standard definition of moderate drinking [31] and residual confounding by other lifestyle factors [32]. In Western populations, moderate alcohol drinkers tend to have a higher education level and socioeconomic status, healthier lifestyles and possibly better cognitive ability than non-drinkers [33]. Additionally, many studies incorporated former drinkers in the non-drinkers reference group, although former drinkers were likely to stop drinking because of health problems [29, 30]. Therefore, the protective effect of moderate drinking on cognition could have been over-estimated [34]. Meanwhile, the ‘optimal’ level of alcohol consumption for protecting cognitive performance may vary according to sex, type of alcohol, drinking pattern and other lifestyle or genetic factors [32, 35]. In Chinese population, a Mendelian randomization study indicated that moderate drinking was unlikely to be cognitively protective [36], and two large cross-sectional studies also failed to find protective association with moderate drinking [37, 38], while another cross-sectional study even found that weekly and daily alcohol drinking were associated with an increased risk of cognitive impairment [25], which is consistent with our finding.
However, most studies that reported combined relation of smoking and drinking have been cross-sectional [39–42] or case-control studies [43, 44] with small sample sizes (n < 2,000), and results remain controversial. Consistent with our findings, in the Whitehall cohort study of 6473 UK adults, participants who were both smokers and heavy drinkers had a 36% faster cognitive decline compared to never smokers who also drank alcohol moderately [16]. Another study among 1314 Finnish adults reported that although moderate drinking was associated with better cognitive function, this benefit was abolished by smoking [17]. A prospective cohort study in a Chinese population also showed that participants who were current smokers and daily drinkers had a 3.9-fold risk of vascular dementia compared with those who did not smoke nor drink daily. Similarly, the elevated risk for vascular dementia was not significant for smokers alone (1.06, 0.77–1.08) or daily drinkers alone (1.03, 0.82–1.07) [15]. The possible synergistic interaction between smoking and alcohol consumption on the risk of cognitive impairment, if validated in future large population-based cohort studies, may help explain the controversy around the association between alcohol consumption and cognitive impairment or dementia without careful consideration of smoking status.
Several mechanistic pathways may illuminate the biological plausibility underlying this finding. First, experimental studies have shown that both alcohol and nicotine can act on nicotinic acetylcholine receptors in the brain, enhancing the function of some receptor subtypes and inhibiting the activity of others, and chronic alcohol and nicotine administration has been associated with changes in the numbers of these receptors [45]. These nicotinic receptors in the brain, in turn, could modulate brain electrical activity and play a role in cognition, memory and attention [46]. Experimental evidence also shows that both nicotine and ethanol can increase dopaminergic neuron firing and dopamine release of the dopaminergic neurons in several brain areas including the nucleus accumbens [47], and activation of the latter has been implicated in changes in emotional and cognitive behaviours [48]. Hence, it is plausible that nicotine and ethanol could be associated with cognitive impairment through their synergistic adverse effects on the dopaminergic and cholinergic systems [49]. Future studies are needed to further elucidate the basic mechanisms for the joint effects of smoking and alcohol consumption on the brain.
The strengths of our study included its prospective study design, large sample size, long follow-up duration and detailed data on potential confounders. We also acknowledge some limitations. First, we could not evaluate the effect of heavy alcohol consumption because of the low prevalence of heavy drinking in our population. Second, the self-reported information of smoking and drinking at enrollment may have changed over time, which could result in some non-differential misclassification, leading to an attenuated association observed in the present study. Third, self-selection and survival bias could exist since we could only include participants who had survived long enough to participate in the follow-up three interviews after about 20 years, and would have excluded those who were unable to participate due to severe cognitive impairment or clinically diagnosed dementia. Fourth, the MMSE testing is known to have limitation for screening cognitive impairment in the general population. Even when MMSE scores are corrected for educational level, they could still have ceiling effects when used for poorly educated people and floor effects for those with higher education [50], and additional testing, such as Montreal Cognitive Assessment (MoCA), may be needed [51]. Fifth, cognitive performance was assessed only once, hence, we cannot evaluate the decline in cognitive function over time. Finally, given that all participants were Chinese and most participants had lower educational attainment, the generalizability of the results to other populations with higher level of education should be made with caution.
In conclusion, we found that concurrent habits of smoking and drinking alcohol at least weekly at midlife were associated with an increased risk of cognitive impairment. Advocating smoking cessation and alcohol abstinence in midlife may be an effective strategy to reduce the development of cognitive impairment with ageing.
Key points.
Smoking in midlife was associated with poorer cognitive performance in later life.
Drinking alcohol at least weekly in midlife was associated with an increased risk of cognitive impairment in later life.
Smoking and alcohol drinking at midlife may have a synergistic adverse effect on the development of cognitive impairment.
Supplementary Material
Acknowledgements
We thank Ms Siew-Hong Low of the National University of Singapore for supervising the fieldwork of the Singapore Chinese Health Study and Dr Renwei Wang for the maintenance of the cohort study database.
Funding
This work was supported by the National Medical Research Council, Singapore (NMRC/CSA/0055/2013), National Cancer Institute, National Institutes of Health, United States (grant numbers UM1 CA182876 and R01 CA144034), and the Saw Swee Hock School of Public Health, National University of Singapore. A.P. is supported by the National Key Research and Development Program of China (2017YFC0907504). The sponsors have no role in: the study design; the collection, analysis or interpretation of data; the writing of the report or in the decision to submit the article for publication.
Conflicts of Interest
None.
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