The design of the Ohsaki Cohort 2006 Study has been described in detail elsewhere . In brief, the source population for the baseline survey comprised 31,694 men and women aged ≥ 65 years who were living both at home and in long-term care settings, in Ohsaki City, north-eastern Japan, on 1 December 2006.
The baseline survey was conducted between 1 December and 15 December 2006, and follow-up of the participants was started from 1 April 2007. A questionnaire was distributed by the heads of individual administrative districts to individual households and then collected by mail. In this analysis, 23,091 persons who provided valid responses formed the study cohort. We excluded 6333 people who did not provide written consent for review of their long-term Care Insurance (LTCI) information, 2102 who had already been certified as having disability by the LTCI before follow-up (1 April 2007), 62 who had died or moved out of the district before follow-up, 192 whose Doctor’s Opinion Paper (DOP) or cognitive status in the DOP were unavailable, 1828 whose data on smoking status were missing, and 85 whose data on years since smoking cessation were missing. Thus, 12,489 participants were finally included in the analysis for the purposes of this study.
Participants were categorized as never smokers, current smokers, or ex-smokers according to their responses on the questionnaires at the baseline. Both current smokers and ex-smokers were asked when they had started smoking, and the average number of cigarettes smoked per day; ex-smokers were also asked the number of years that had passed since they had quit. We initially intended to categorize ex-smokers into “≤ 5 years”, “6–10 years”, “11–15 years”, and “> 15 years”, but previous studies have indicated that an even shorter period of smoking cessation can benefit cognitive function [20, 22]. Thus, we decided to further divide “≤ 5 years” into two separate groups, “≤ 2 years” and “3–5 years”. Additionally, we also calculated cumulative smoking pack-years (the average number of cigarettes smoked per day divided by 20 and multiplied by the number of years of smoking) among both current smokers and ex-smokers, and considered never smokers as 0 pack-years.
Follow-up (incident dementia)
The primary outcome was incident dementia, defined as disabling dementia according to the criteria of the LTCI system that has been implemented in Japan since April 2000 . The LTCI is a mandatory form of national social insurance to assist activities of daily living (ADLs) in the disabled elderly [24,25,26]. Everyone aged 40 years or older pays premiums and everyone aged 65 years or older is eligible for formal caregiving services under a uniform standard of disability certification. The procedure for disability certification comprises two parts: assessment of the degree of functional disability using a questionnaire developed by the Ministry of Health, Labour and Welfare, and reference to the DOP prepared by the attending physician . The DOP is a standard form used for assessing patients’ chronic medical conditions and functions of daily life.
Disabling dementia was defined as incident functional disability with dementia according to the LTCI system, whereby the dementia exceeded rank I (≥ rank II) on the Dementia Scale (Degree of Independence in Daily Living for Elderly with Dementia), as entered on the DOP. The Dementia Scale is classified into six ranks: 0, I–IV, M; Rank M means that an individual has severe dementia-related behavioural disturbance that requires medical intervention, and a rank exceeding I is typically used as an outcome measure of incident dementia because individuals who have mild or moderate dementia are classified as rank II [23, 28,29,30]. A previous study reported that the Dementia Scale had a sensitivity (95% CI) of 73% (65–80%) and a specificity of 96% (94–97%) against clinical diagnoses by neuropsychiatrists who used a clinical interview as defined by the International Psychogeriatric Association .
We obtained a dataset that included information on LTCI certification, death or emigration from Ohsaki City. All data were transferred from the Ohsaki City Government under an agreement related to Epidemiologic Research and Privacy Protection.
Body mass index (BMI) was calculated as the self-reported body weight (kg) divided by the square of the self-reported body height (m) and BMI ≥ 25 kg/m2 was defined as obesity. Time spent walking was evaluated by asking the question, ‘How long do you walk per day, on average?’, for which the participants chose one of three responses: ‘< 0.5 h’, ‘0.5–1 h’ or ‘≥ 1 h’. Alcohol drinking status was also obtained by asking the question, “Do you drink alcohol?”, for which the participants chose one of three responses: ‘yes’, ‘abstain’ or ‘no’. The participants were also asked about whether they had ever suffered from the following diseases: stroke, myocardial infarction (MI), hypertension (individuals with self-measured systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg were also defined as hypertensive) or diabetes. Education level was assessed using the question, “How old were you when you left school?” and based on the responses, we further divided the participants into junior high school or less (< 16 years), high school (16–18 years) or college or higher (≥ 19 years). Psychological distress was measured using the Kessler 6-item Psychological Distress Scale [32, 33]. Using six questions, respondents were asked about their mental status over the previous month. Total point scores ranged from 0 to 24. Based on the optimal cut-off point for mental illness in the validation study, we classified individuals with scores of ≥ 13 as having psychological distress .
Cognitive function was measured using items from the Kihon Checklist, which was developed by the Ministry of Health, Labour, and Welfare of Japan to predict functional decline in community-dwelling elderly. Respondents were asked about their current subjective memory complaints by using three binary questions yielding total point scores ranging from 0 to 3. The validity of the cognitive function score in the Kihon Checklist had been confirmed in a previous study using the Clinical Dementia Rating as a gold standard .
Informed consent was obtained from all individual participants included in the study. We considered the return of completed questionnaires to imply consent to participate in the study involving the baseline survey data and subsequent follow-up of death and emigration. We also confirmed information regarding LTCI certification status after obtaining written consent along with the questionnaires returned from subjects at the time of the baseline survey in 2006. The Ethics Committee of Tohoku University Graduate School of Medicine (Sendai, Japan) reviewed and approved the study protocol. (Approval No.2016-1-586).
We counted the person-years of follow-up for each subject from 1 April 2007 until the date of incident dementia, date of emigration from Ohsaki City, date of death, incident functional disability without dementia or the end of the study period (30 November 2012), whichever occurred first.
The multivariable-adjusted Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident dementia according to smoking status. Dummy variables were created for the smoking status groups, and never smokers were defined as a reference category. Time of follow-up was used as the time scale in the corresponding models. Multivariable models were adjusted for the following variables. Model 1 was adjusted for sex and age (continuous). To examine whether the association between smoking status and dementia was attributable to lifestyle factors and other health-related factors, model 2 was further adjusted for obesity, time spent walking per day, alcohol drinking status, education level, history of diseases (stroke, MI, hypertension, or diabetes), and psychological stress score.
Smoking is a significant risk factor for death, and some severe diseases that can cause disability and death without disability, as well as non-dementia disability, were censored during follow-up before the onset of dementia in our study. Accordingly, it is necessary to examine the possible influence of competing events on the association between smoking status and risk of incident dementia applying Fine and Gray’s subdistribution hazards regression model . Competing events were defined as: (1) death without disability, (2) any other types of disability and (3) death and any other types of disability.
Four sets of sensitivity analyses were undertaken. First, considering possible reverse causality, people with higher cognitive function are more likely than those with lower cognitive function to quit smoking, we analyzed whether the association would change if only individuals who had higher cognitive function at the baseline were selected; in this sensitivity analysis, “Cognitive function score in the Kihon Checklist = 0 points” was defined as better cognitive function. Second, we reanalyzed the association between smoking cessation and dementia by excluding participants whose dementia event occurred in the first 2 years of follow-up. Third, considering that smoking prevalence differs according to sex, age, education level and cardiovascular risk factors (CRFs), and that education and CRFs are also important factors related to incident dementia, we stratified participants according to sex, age (< 75 years or ≥ 75 years), education level (< junior higher school or ≥ junior high school), history of stroke or MI (at least one of them), hypertension, and diabetes. Tests of interaction were also performed in terms of sex, age, education level, and history of diseases mentioned above. Lastly, to explore further the continuous relationship between years since smoking cessation and incident risk of dementia, penalized splines (P-splines) were used where automatic selection criteria for deciding the optimal degree of smoothing (or equivalently, the optimal degrees of freedom) were implemented .
In addition, previous studies also suggest that cumulative smoking pack-years was related to cognitive function . Therefore, we also applied multivariable Cox models to examine the relationship between cumulative smoking pack-years and incident dementia, with never smokers as the reference group.
All of the above analyses were performed using SAS version 9.4 (SAS Inc.), and P-splines were drawn by smoothHR package using R version 3.5.2. All statistical tests described here were two-sided, and differences at P < 0.05 were accepted as statistically significant.