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CHILDHOOD SECONDHAND SMOKE EXPOSURE AND RISK OF DEMENTIA, ALZHEIMER’S DISEASE AND STROKE IN ADULTHOOD: A PROSPECTIVE COHORT STUDY

 

S. Zhou1, K. Wang2

 
1. Department of Respiratory and Critical Care Medicine, the Second People’s Hospital of Yibin/West China Yibin Hospital, Sichuan University, Yibin, Sichuan, China; 2. Department of Neurosurgery, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA, ORCID ID is 0000-0002-6958-7677

Corresponding Author: Kanran Wang, MD, Department of Neurosurgery, Harvard Medical School and Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA, 02115, kankans93@163.com
J Prev Alz Dis 2021;
Published online March 24, 2021, http://dx.doi.org/10.14283/jpad.2021.10

 


Abstract

Background: This study aimed to investigate the associations between secondhand smoke exposure and dementia, Alzheimer’s disease (AD) and stroke.
Methods: This prospective study analyzed Framingham Offspring (FHS-OS) cohort participants with parents in the original Framingham Heart Study (FHS) cohort with known smoking status during offspring childhood. Surveillance for incident events, including dementia and stroke, among offspring participants exposed to parental smoking up to the age of 18 years commenced at examination 9 through 2014 and continued for approximately 30 years.
Results: At baseline, a total of 1683 (56.2%) subjects were not exposed to any secondhand smoke, whereas 670 (22.4%) subjects were exposed to 0-1 packs (20 cigarettes)/day, and 640 (21.4%) were exposed to over 1 pack/day. On follow-up (median: 31 years), 2993 patients developed dementia, including 103 with AD dementia and 315 with stroke. After adjusting for a wide range of established risk factors, participants with the highest exposure to secondhand smoke exhibited increased risks of all dementia, AD dementia and stroke compared with individuals with no exposure [HR 2.86 (2.00-4.09) for dementia; HR 3.13 (1.80-5.42) for AD dementia; HR 1.89 (1.37-2.61) for stroke]. The results remained comparable in the subgroup for individuals with median exposure to secondhand smoke.
Conclusion: Exposure to secondhand smoke may be associated with increased risks of dementia, AD dementia and stroke.

Key words: Secondhand smoke, Dementia, Alzheimer disease, stroke, cohort study.


 

Introduction

Dementia is a common neurodegenerative disease, and it is estimated that the number of cases will reach approximately 81.1 million by 2040 with a complicated etiology underpinned by genetic and environmental components (1-3). In the past decade, the prevention and exploration of risk factors for dementia has been increasingly receiving attention in the field (4-6).

The smoking-dementia relationship has been investigated by many studies, and cigarette smoking remains one of the most important modifiable risk factors for incident dementia and AD (7, 8). Moreover, exposure to secondhand smoke has also been shown to alter the risk of cardiovascular and metabolic diseases (9-11). However, only a few reports have been published on the effects of secondhand smoke exposure on dementia and AD. A national cross-sectional study reported that exposure to secondhand smoke may be associated with increased odds of cognitive impairment, which relied on self-reported cigarette smoke exposure; therefore, recall bias may have played a role (12). Both stroke and dementia share common risk factors and etiologies (13), but the longitudinal relationship between exposure to secondhand smoke and the risk for stroke was also insufficiently verified. Thus, the potential effects of long-term and accurately evaluated exposure to secondhand smoke on the risk for dementia and stroke remain largely unexplored.
We therefore sought to leverage the multigenerational Framingham Heart Study to test the association between exposure to secondhand smoke and long-term risk (i.e., over 30 years) of dementia and AD and stroke with a detailed review of all medical records and precise assessment of secondhand smoke.

 

Methods

Study Design

We used data from the Framingham Heart Study (FHS), which commenced in 1948 with the enrollment of 5,209 original cohort participants in the Framingham, Massachusetts and Framingham Heart Study offspring (FHS-OS) cohort, which was established in 1970 and includes 5124 individuals who were the offspring of the FHS original cohort and their spouses (14, 15). These cohorts as well as their design and methods were described in greater detail elsewhere (16). Briefly, since their recruitment, participants from the FHS cohort have had serial examinations every 2-4 years and the FHS-OS cohort every 4-8 years, including standardized interviews, physician examinations and laboratory tests. For the present investigation, we included participants of the FHS-OS cohort with at least 1 parent in the FHS original cohort with a known smoking status at any point until his or her offspring reached the age of 18 years. The most recent examination period for both the FHS and FHS-OS cohorts concluded in 2014. This study complied with the Declaration of Helsinki; written informed consent was obtained from all study participants. This current study utilizing the Framingham Heart Study datasets was approved by the National Heart, Lung, and Blood Institute (NHLBI) of National Institutes of Health (NIH).

Smoking Assessment

Smoking was defined in both the FHS and FHS-OS cohorts as participants reporting smoking >1 cigarette daily during the year prior to their study examination. For those participants who reported smoking, the number of mean packs of cigarettes smoked per day was calculated based on the daily number of cigarettes (1 pack representing 20 cigarettes). Parental smoke exposure for the FHS-OS cohort was assessed and defined as the presence of parental smoking (either parent) of greater than 0 mean packs/day at any point in an examination period when his or her offspring participant was between 0 and 18 years of age. To account for a possible dose-response smoking relationship from variable exposure between individual parents, parental smoke exposure was also defined as the summation of the number of cigarettes smoked daily by both the mother and father, which was further categorized into a three-level variable: no exposure, 0-1 pack/day and >1 pack/day. Baseline offspring smoking status was defined as smoking of >0 mean packs per day in Exam 1 of the FHS-OS cohort. Details were further described in the FHS-OS protocol (https://biolincc.nhlbi.nih.gov/studies/framoffspring/Protocols/).

Ascertainment of Dementia and AD

Participants in the FHS-OS were under ongoing continuous surveillance for the onset of cognitive impairment and clinical dementia. We related childhood secondhand smoke exposure to the long-term risk of dementia and AD dementia. A diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. A diagnosis of Alzheimer’s disease (AD) dementia was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association for definite, probable, or possible AD (17, 18).

Ascertainment of Stroke

Stroke incidence was assessed through the continuous monitoring of hospital admissions in Framingham and by reviewing all available outside medical records and interim hospitalizations (19). Stroke was defined as focal neurological symptoms of rapid onset and presumed vascular origin lasting >24 hours or resulting in death within 24 hours. A committee comprising at least 3 FHS investigators, including at least 2 neurologists, adjudicated stroke diagnosis. The committee considered all available medical records, brain imaging, cerebrovascular imaging, and the assessment of the study neurologist who visited the participant.

Covariates

The following dementia and/or stroke risk factors at Exam 1 in the FHS-OS cohort were utilized as baseline covariates in the study analysis: hypertension, diabetes mellitus, body mass index (BMI), waist circumference, alcohol consumption, current smoking status, blood lipids and education level. Hypertension was confirmed as systolic blood pressure>140 mm Hg, diastolic blood pressure>90 mm Hg, or use of antihypertensive medications. Individuals with fasting plasma glucose concentrations ≥7 mmol/L or who self-reported the use of antidiabetic medications were considered diabetic. BMI was calculated as weight in kilograms divided by the square of the participant’s height in meters at baseline examination. Waist circumference (in inches) was measured at the level of the umbilicus. Current smokers were defined as participants who smoked regularly during the year before the examination (yes or no) as assessed via questionnaire in all serial examination cycles. The educational level was assessed by medical interview. Total cholesterol and low-density lipoprotein cholesterol were measured after an overnight (>10 hours) fast.

Statistical Analysis

Descriptive statistics were performed for the 3 subgroups: participants with no exposure to secondhand smoke, 0-1 pack/day and >1 pack/day. Continuous and ordinal variables are expressed as the mean ± SD or median (interquartile range), respectively. The chi-square test was used to compare categorical variables, and Fisher’s exact test was used for categories with <5 observations. Follow-up for dementia and stroke was from the baseline examination to the time of incident event. For persons with no incident events, follow-up was censored at the time of death or the date the participant was last known to be dementia free. For survival analysis, Cox proportional hazards modeling was applied, and the following covariates were included: crude analysis; model 1 adjusted for age and sex; and model 2 adjusted for age, sex, and the following dementia risk factors: hypertension, smoking, diabetes and body mass index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The same analysis was performed for Alzheimer’s disease and stroke. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL, USA) and Stata statistical software, version 15 (Stata Corporation, College Station, Texas, USA). A 2-sided P<0.05 was considered statistically significant.

 

Results

Subjects

Of the 3765 participants of the FHS Offspring Cohort attending the baseline exam until older than 18 years old, the condition of parental smoking was ascertained in 3545 subjects. Thus, these participants were included in this study. Therefore, 552 subjects were excluded because 498 subjects lacked assessment of dementia or stroke, 4 subjects were diagnosed with dementia at baseline, 3 with stroke, and 50 subjects were lost to follow-up for dementia or stroke. Finally, 2993 individuals could be included in the analyses with 1683 (56.2%) subjects with no secondhand smoke exposure, 670 (22.4%) subjects with exposure to 0-1 packs/day and 640 (21.4%) subjects with over 1 pack/day. (Figure 1)

Figure 1. Selection of Study Participants in the Framingham Heart Study

 

Table 1 shows the characteristics of those included in the analysis. The three groups descriptively differed with regard to age, sex, systolic blood pressure, diastolic blood pressure, smoking status and history of hypertension. In detail, in trends from the lowest to the highest exposure of secondhand smoking, those exposed to secondhand smoke were more likely to be slightly younger, female, with an increased incidence of blood pressure and hypertension but not diabetes and differ metabolic indicators, including LDL and TC. Finally, those exposed to secondhand smoke were more likely to be smokers themselves, and no difference was shown in alcohol consumption.

Table 1. Characteristics of the study sample of the Framingham Heart Study at baseline secondhand smoke exposure assessment

Abbreviations: BMI, body mass index; WC, waist circumference. LDL, low-density lipoprotein, TC: total cholesterol.

 

Secondhand smoke exposure and risk for dementia and stroke

Among the FHS-OS cohort with available smoking ascertainment, 239 (8.0%) developed dementia, including 103 with AD dementia over a median follow-up of 31 years (interquartile range, 28 to 32 years), with an overall incidence rate of 3.32 per 1,000 person-years. In addition, 315 (10.5%) cases of incident stroke were identified over a median follow-up of 31 years (interquartile range, 30 to 32 years) with an overall incidence rate of 3.53 per 1,000 person-years.
Risks of incident dementia, AD dementia and stroke according to secondhand smoke exposure are presented in Table 2. After adjusting for offspring age, sex, BMI, diabetes, smoking and hypertension, parental smoking greater than 1 pack/day was associated with significantly increased risks of offspring dementia, AD dementia and stroke [HR 2.86 (2.00-4.09) for dementia; HR 3.13 (1.80-5.42) for AD dementia; HR 1.89 (1.37-2.61) for stroke] compared with subjects without exposure for secondhand smoke. These trends remained the same for participants with parental smoking between 0 and 1 pack/day [HR 1.79 (1.21-2.64) for all dementia; 1.97 (1.09-3.58) for AD dementia; 1.60 (1.17-2.19) for stroke]. In an additional sensitivity analysis, all analyses in the subgroup of nonsmokers in offspring were repeated, and results consistent with the whole population were obtained. (eTable 1 in the supplement) The cumulative incidence curves for all dementia, AD dementia and stroke stratified by groups with different levels of exposure to secondhand smoke showed consistent results with the Cox regression after adjusting for age and sex. (Figure 2.)

Table 2. Cumulative hazards based on secondhand smoke exposure

Abbreviations: AD, Alzheimer’s disease; HR, hazard ratio; CI, confidence interval; Model 1 Sex and Age; Model 2 in addition for hypertension, smoking, diabetes and body mass index.

 

Figure 1. Adjusted cumulative incidence of dementia and stroke based on secondhand smoke exposure

 

Discussion

In this prospective community-based and multigenerational sample with a median follow-up time of almost 30 years, exposure to secondhand smoke was associated with increased risks of offspring dementia, AD dementia and stroke after adjustment for conventional risk factors and accounting for dementia or stroke clustering within families.
These findings highlight potential new mechanistic pathways for dementia and stroke risk that begin during childhood and an association between secondhand smoke exposure and dementia and/or stroke risk. These observations may also provide new information pertinent to smoking cessation and avoidance more than relationship may be mediated by a greater tendency among their posterity of smoking parents to smoke themselves (20), highlighting the harms that may be associated not only to irrelevant strangers but to close and the most vulnerable members of the family.
Despite the published health hazards of smoking and public awareness campaigns to reduce smoking, 52.1% of Chinese men and 14% of US adults continue to smoke (21, 22). Smoking remains the primary cause of preventable death with the number of attributable annual deaths expected to increase to 8 million by 2030 (23). However, we often overlook that secondhand smoke exposure reached 54.3% in the workplace and 57.1% at home in 2015 in China and is responsible for at least 41,000 deaths annually in the US (22, 24). While there have been numerous published reports of the deleterious effects of secondhand smoke exposure on chronic kidney disease (25), cancer and other cardiovascular conditions, such as coronary heart disease (26, 27), the risk of dementia and stroke secondary to is less well defined. A national cross-sectional study from the UK demonstrated that exposure to secondhand smoke may be associated with increased odds of cognitive impairment after adjustment for a wide range of established risk factors for cognitive impairment. A secondary analysis including 970 US participants in the Cardiovascular Health Cognition Study found that exposure to high levels of secondhand smoke alone would increase the risk of dementia in elderly individuals with a history of carotid artery stenosis but not in the general population. A prospective cohort study including 7000 permanent residents from six regions within Zhejiang Province, China showed that passive smoking exposure increased the risk of cognitive impairment in older adults, especially nonsmokers (28). To our knowledge, this is the first study to demonstrate a significant association between secondhand smoke exposure and all dementia, AD dementia and stroke development in a prospective observation of a large-scale cohort with accurate assessments for secondhand smoke based on well-organized original and offspring cohorts.
Given that smoking is widely recognized a risk factor for dementia and stroke, we hypothesize that these mechanisms should be no less relevant during passive smoke inhalation and that this may be even more critical during early human growth and development in the childhood and adolescent years. First, secondhand smoke is highly noxious and contains greater than 250 chemicals known to be harmful or carcinogenic (29, 30). Therefore, such exposure could negatively impact the brain and nerves in a direct manner that could result in dementia and stroke. Moreover, exposure to secondhand smoke is a previously established risk factor for coronary heart disease and diabetes mellitus (31), each of which is an important risk factor for cognitive impairment, dementia and stroke and thus may indirectly affect the risk (32, 33). Finally, regarding basic research, secondhand smoke exposure adversely affects endothelial function and contributes to vasoconstriction, atherogenesis, and thrombosis and may therefore compromise the blood supply to the brain (34, 35). Moreover, endothelial dysfunction may lead to the reduced clearance of β-amyloid protein, which is considered to be related to the pathogenesis of Alzheimer’s disease (36). Taken together, there are several mechanisms through which secondhand smoke could directly and indirectly affect dementia risk. In a large, dementia-free multigenerational cohort, our results provide further evidence that secondhand smoke is associated with an increased risk of all dementia, AD dementia and stroke after adjustment for confounders, including sex, age, BMI, diabetes and hypertension.
The strengths of the study include a large heterogeneous sample size; a unique longitudinal, community-based cohort spanning generations; and long-term and robust follow-up for our outcomes of interest. Moreover, the FHS and FHS-OS cohorts were renowned for their precise ascertainment of relevant covariates that may be potential confounders used in multivariable adjustment.

Limitations

First, parental smoking status was unclear in some potentially exposed offspring participants, and the number of incident events was small, which may lead to selection bias. Second, the observational nature of our study prevents us from inferring causal links between exposure to secondhand smoke and the risks of dementia and stroke. Finally, although we addressed confounding in numerous ways, we cannot exclude the possibility of residual confounding, especially for certain dementia and/or risk factors that were not available to us based on public databases, such as genotype ApoE4 (37). Therefore, larger studies are needed to replicate and verify our results.

 

Conclusions

Our study demonstrates that early-life exposure to secondhand smoke was significantly associated with increased risks of dementia, AD dementia and stroke development. International policy debate on exposure to secondhand is a topic of major public health significance. Dementia and stroke are two of the largest global public health challenges facing our aging population. These findings may provide new evidence to reduce the risk of secondhand smoke exposure by enhancing public smoking restriction policies and motivating current smokers to quit as well as motivating potential smokers to avoid smoking altogether to maintain better health.

 

Acknowledgments: The authors thank the National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, and the Second People’s Hospital of Yibin/West China Yibin Hospital, Yibin, Sichuan.

Data Availability: Data described in the manuscript, code book, and analytic code will not be made available because the authors are prohibited from distributing or transferring the data and codebooks on which their research was based to any other individual or entity under the terms of an approved NHLBI Framingham Heart Study Research Proposal and Data and Materials Distribution Agreement through which the authors obtained these data.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: SF Zhou. Critical revision of the manuscript for important intellectual content: KR Wang. Statistical analysis: KR Wang. Obtained funding: KR Wang. Supervision: KR Wang. Grant Support: None. All authors have read the journal’s authorship agreement, and the manuscript has been reviewed by and approved by all named authors.

Ethical Standards: The study procedures followed were in accordance with the ethical standards of the Institutional Review Board and the Principles of the Declaration of Helsinki.

Conflicts of Interest: The authors declare that they have no conflicts of interest.

 
SUPPLEMENTARY MATERIAL
 

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