Consumption of coffee and tea and risk of developing stroke, dementia, and poststroke dementia: A cohort study in the UK Biobank.

BACKGROUND: Previous studies have revealed the involvement of coffee and tea in the development of stroke and dementia. However, little is known about the association between the combination of coffee and tea and the risk of stroke, dementia, and poststroke dementia. Therefore, we aimed to investigate the associations of coffee and tea separately and in combination with the risk of developing stroke and dementia. METHODS AND
FINDINGS: This prospective cohort study included 365,682 participants (50 to 74 years old) from the UK Biobank. Participants joined the study from 2006 to 2010 and were followed up until 2020. We used Cox proportional hazards models to estimate the associations between coffee/tea consumption and incident stroke and dementia, adjusting for sex, age, ethnicity, qualification, income, body mass index (BMI), physical activity, alcohol status, smoking status, diet pattern, consumption of sugar-sweetened beverages, high-density lipoprotein (HDL), low-density lipoprotein (LDL), history of cancer, history of diabetes, history of cardiovascular arterial disease (CAD), and hypertension. Coffee and tea consumption was assessed at baseline. During a median follow-up of 11.4 years for new onset disease, 5,079 participants developed dementia, and 10,053 participants developed stroke. The associations of coffee and tea with stroke and dementia were nonlinear (P for nonlinear <0.01), and coffee intake of 2 to 3 cups/d or tea intake of 3 to 5 cups/d or their combination intake of 4 to 6 cups/d were linked with the lowest hazard ratio (HR) of incident stroke and dementia. Compared with those who did not drink tea and coffee, drinking 2 to 3 cups of coffee and 2 to 3 cups of tea per day was associated with a 32% (HR 0.68, 95% CI, 0.59 to 0.79; P < 0.001) lower risk of stroke and a 28% (HR, 0.72, 95% CI, 0.59 to 0.89; P = 0.002) lower risk of dementia. Moreover, the combination of coffee and tea consumption was associated with lower risk of ischemic stroke and vascular dementia. Additionally, the combination of tea and coffee was associated with a lower risk of poststroke dementia, with the lowest risk of incident poststroke dementia at a daily consumption level of 3 to 6 cups of coffee and tea (HR, 0.52, 95% CI, 0.32 to 0.83; P = 0.007). The main limitations were that coffee and tea intake was self-reported at baseline and may not reflect long-term consumption patterns, unmeasured confounders in observational studies may result in biased effect estimates, and UK Biobank participants are not representative of the whole United Kingdom population.
CONCLUSIONS: We found that drinking coffee and tea separately or in combination were associated with lower risk of stroke and dementia. Intake of coffee alone or in combination with tea was associated with lower risk of poststroke dementia.

Introduction

Dementia is characterized by a progressive and unrelenting deterioration of mental capacity that inevitably compromises independent living [1]. Alzheimer disease and vascular dementia are the 2 main subtypes of dementia. Dementia is more of a clinical symptom than a specific disease and can be induced by cerebral degeneration, cerebrovascular diseases, traumatic brain injury, brain tumors, intracranial infection, metabolic diseases, and poisons. With the aging population trend, dementia has become an increasing global health concern and brought a heavy economic and social burden. Globally, over 50 million individuals had dementia in 2019. This number is anticipated to increase to 152 million by 2050 [2]. Given the limited therapeutic value of drugs currently used for treating dementia, identifying the preventable risk factors of dementia is of high priority.

Stroke, accounting for 10% of all deaths globally [3], is a leading cause of all disability-adjusted life years [4]. Although the age-standardized incidence and mortality of stroke have decreased globally in the past 2 decades, the absolute numbers of stroke cases and deaths have increased [5]. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. A population-based longitudinal study found that stroke and dementia shared about 60% risk and protective factors [6]. In principle, 90% of strokes and 35% of dementia have been estimated to be preventable [7-10]. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementia cases could be prevented by preventing stroke [10].

Coffee and tea are among the most widely consumed beverages, both in the UK and worldwide. Coffee contains caffeine and is a rich source of antioxidants and other bioactive compounds [11]. Tea containing caffeine, catechin polyphenols, and flavonoids has been reported to play neuroprotective roles, such as antioxidative stress, anti-inflammation, inhibition of amyloid-beta aggregation, and an antiapoptotic effect [12]. Coffee consumption is closely related to tea consumption. A prospective cohort study reported that approximately 70% of participants consumed both coffee and tea [13]. Coffee and tea are distinct beverages with overlapping components, such as caffeine, and different biologically active constituents, including epigallocatechin gallate and chlorogenic acid [14]. These constituents appeared to share common mechanisms—reactive oxygen species, on the other hand, different constituents also have different target molecules and therefore different biological effects [14]. Furthermore, genetic polymorphisms in enzymes that involved in uptake, metabolism, and excretion of tea and coffee components were also associated with the differential biological activities of the 2 beverages [15]. Additionally, studies have found the interaction between green tea and coffee on health outcomes in the Japanese population [13,16]. The Japan public health center-based study cohort reported that there was a multiplicative interaction between green tea and coffee that was associated with a lower risk of intracerebral hemorrhage [16]. A prospective study demonstrated that there appear to be an additive interaction between green tea and coffee on mortality in Japanese patients with type 2 diabetes [13]. Epidemiological and clinical studies have shown the benefits of coffee and tea separately in preventing dementia [17-22]. However, little is known about the association between the combination of coffee and tea and the risk of dementia. Therefore, we aimed to explore the association between the combination of coffee and tea, which could be multiplicative or additive interaction, and the risk of stroke and dementia.

Poststroke dementia refers to any dementia occurring after stroke [23]. Poststroke dementia poses a significant public health problem, with 30% of stroke survivors suffering from dementia [23,24]. Thus, identifying and preventing the influencing factors of poststroke dementia are quite important. Epidemiological studies have found inverse associations between coffee and tea and incident stroke and dementia [25-28], but the associations between coffee and tea intake and incident poststroke dementia remain unclear. Therefore, the purpose of this study was to investigate the associations of coffee and tea separately and in combination with the risk of developing stroke, dementia, and poststroke dementia based on data from a large population-based cohort.

Methods

This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (). UK Biobank has ethics approval from the North West Multi-Centre Research Ethics Committee (11/NW/0382). Appropriate informed consent was obtained from participants, and ethical approval was covered by the UK Biobank. This research has been conducted using the UK Biobank Resource under the project number of 45676. The analysis plan was drafted prospectively in February 2020 ().

Study design and population

The UK Biobank comprises data from a population-based cohort study that recruited more than 500,000 participants (39 to 74 years old) who attended 1 of the 22 assessment centers across the UK between 2006 and 2010 [29]. The analyses were restricted to individuals who were at least 50 years old at baseline (because most incident dementia and stroke cases occur in older adults). Participants provided extensive information via questionnaires, interviews, health records, physical measures, and blood samples. Data from individuals with self-reported prevalent stroke or dementia at baseline or a diagnosis of stroke or dementia identified in hospital records were excluded from analyses in our present study. Data from 365,682 individuals were available for analyses in our present study.

Exposure assessment

Coffee intake was assessed at baseline using a touchscreen questionnaire. Participants were asked, “How many cups of coffee do you drink each day (including decaffeinated coffee)?” Participants selected one of the following: “Less than one,” “Do not know,” “Prefer not to answer,” or specific number of cups of coffee drinking per day. If participants reported drinking more than 10 cups each day, they were asked to confirm their response. In addition, coffee drinkers were also asked “what type of coffee do you usually drink?” and were then instructed to select 1 of 6 mutually exclusive responses, as follows: “Decaffeinated coffee (any type),” “Instant coffee,” “Ground coffee (include espresso and filtered coffee), “other type of coffee,” “Do not know,” or “prefer not to answer.” We then analyzed the associations among different coffee types and the risk of incident stroke and dementia.

Tea intake was assessed at baseline using a touchscreen questionnaire. Participants were asked, “How many cups of tea do you drink each day (including black and green tea)?” Participants selected one of the following: “Less than one,” “Do not know,” “Prefer not to answer,” or specific number of cups of tea drinking per day. If participants reported drinking more than 10 cups each day, they were asked to confirm their response.

Incident stroke and dementia outcomes

Outcomes were ascertained using hospital inpatient records containing data on admissions and diagnoses obtained from the Hospital Episode Statistics for England, the Scottish Morbidity Record data for Scotland, and the Patient Episode Database for Wales. Diagnoses were recorded using the International Classification of Diseases-10th revision (ICD-10) coding system. The primary outcomes in this study were incident stroke and its 2 major component end points—ischemic stroke and hemorrhage stroke, dementia, and its 2 major component end points—Alzheimer disease and vascular dementia. Furthermore, outcomes of incident Alzheimer disease, vascular dementia, ischemic stroke, and hemorrhagic stroke were assessed separately. We defined outcomes according to the ICD-10: stroke (I60, I61, I62.9, I63, I64, I67.8, I69.0, and I69.3), ischemic stroke (I63), hemorrhagic stroke (I60 and I62.9), dementia (F00, F01, F02, F03, F05.1, G30, G31.1, and G31.8), Alzheimer disease (F00 and G30), and vascular dementia (F01).

Covariates

In the present study, the selection of covariates based on (1) demographic variables, including sex, age, ethnicity background, education level, and income; and (2) a priori knowledge of potential confounding factors associated with incident stroke and dementia [30,31]. Covariates were documented including sex, age, ethnicity (White, Asian or Asian British, Black or Black British, and Other ethnic group), qualification (college or university degree, Advanced [A] levels/Advanced Subsidiary [AS] levels or equivalent, Ordinary [O] levels/General Certificate of Secondary Education [GCSE] or equivalent, Certificate of Secondary Education [CSE] or equivalent, National Vocational Qualification [NVQ] or Higher National Diploma [HND] or Higher National Certificate [HNC] or equivalent, other professional qualifications, or none of the above), income (less than £18,000, 18,000 to 30,999, 31,000 to 51,999, 52,000 to 100,000, and greater than 100,000), BMI (<25, 25 to <30, 30 to <35, and ≥35 kg/m2), smoking status (never, former, and current), alcohol status (never, former, and current), physical activity (low, moderate, and high), consumption of sugar-sweetened beverages, history of diabetes, history of coronary artery disease, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and diet pattern (healthy and unhealthy, healthy diet was based on consumption of at least 4 of 7 dietary components: (1) fruits: ≥3 servings/day; (2) vegetables: ≥3 servings/day; (3) fish: ≥2 servings/week; (4) processed meats: ≤1 serving/week; (5) unprocessed red meats: ≤1.5 servings/week; (6) whole grains: ≥3 servings/day; (7) refined grains: ≤1.5 servings/day [32-35]) ().

Information on cardiovascular arterial disease (CAD) was derived from medical records (ICD-10 codes I20 to I25). Diabetes was ascertained on the basis of medical records (ICD-10 codes E10 to E14), glycated hemoglobin ≥6.5%, and the use of antidiabetic drugs. Hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg, use of antihypertension agents, or medical records (ICD-10 codes I10 to I13 and I15). Cancer was identified through linkage to the National Health Service (NHS) Central Register (ICD-10 codes C00 to C97).

Statistical analyses

Baseline characteristics of the samples were summarized across tea and coffee intake as percentages for categorical variables and means and standard deviations (SDs) for continuous variables. Baseline characteristics of the study population were compared across coffee or tea intake categories using analysis of variance (ANOVA) or Mann–Whitney U test for continuous variables and chi-squared tests for categorical variables. Restricted cubic spline models were used to evaluate the relationship between coffee, tea, and their combination and incident stroke and dementia, with 4 knots at the 25th, 50th, 75th, and 95th centiles. In the spline models, we adjusted for sex, age, ethnicity, education, income, body mass index (BMI), physical activity, alcohol status, smoking status, diet pattern, consumption of sugar-sweetened beverages, HDL, LDL, history of cancer, history of diabetes, history of CAD, and hypertension; further, we adjusted for coffee in tea analysis or tea in coffee analysis. To analyze the association between coffee and tea intake categories and new onset outcomes, we defined coffee and tea intake into the following categories: 0, 0.5 to 1, 2 to 3, and ≥4 cups/day. We used Cox proportional hazard models to estimate the associations of coffee and tea intake categories with the incidence of stroke and dementia. The proportional hazards assumptions for the Cox model were tested using Schoenfeld residuals method; no violation of the assumption was observed. The duration of follow-up was calculated as a timescale between the baseline assessment and the first event of stroke or dementia, death, loss of follow-up, or on June 31, 2020, which was the last hospital admission date. Cox regression models were adjusted for sex, age, ethnicity, qualification, income, BMI, physical activity, alcohol status, smoking status, history of cancer, history of diabetes, history of CAD, HDL, LDL, diet pattern, consumption of sugar-sweetened beverages, and hypertension, and we adjusted for coffee in tea analysis or for tea in coffee analysis. If covariate information was missing (<20%), we used multiple imputations based on 5 replications and a chained equation method in the R MI procedure to account for missing data. Detailed information on missing data was shown in . We also used Cox regression to assess the association of coffee and tea with dementia among individuals with stroke. The P-value used for heterogeneity corresponded to the chi-squared test statistic for the likelihood ratio test comparing models with and without interaction between coffee and tea.

Several additional analyses were performed to assess the robustness of our study results. First, we used stratification analysis to examine whether the association between tea and coffee and the risk of stroke and dementia varied by age (<65 versus ≥65 years), sex, smoking status, alcohol status, physical activity, BMI, and diet pattern. The risks of incident stroke and dementia were explored in a series of sensitivity analyses by excluding participants with major prior diseases (e.g., diabetes, CAD, and cancer) at baseline and excluding events occurring during the first 2 years of follow-up. Additionally, we performed the analysis by including participants younger than 50 years old and conducted the analysis with additional more detail adjustment for smoking (never smokers, former smokers quitted >5 years ago, former smokers quitted ≤5 years, current smokers <10 cigarettes per day, current smokers 10 to 20 cigarettes per day, and current smokers 20+ cigarettes per day) and alcohol status (never drinkers, former drinkers, current drinkers <7 g per day, current drinkers 7 to 16 g per day, and current drinkers >16 g per day). Finally, we assessed the competing risk of nonstroke or nondementia death on the association between the combination of tea and coffee and the risks of stroke and dementia using the subdistribution method proposed by Fine and Grey [36]. All P-values were 2 sided, with statistical significance set at less than 0.05. All the analyses were performed using R software, version 3.6.1, and STATA 15.

Results

At baseline, 502, 507 participants were assessed. After excluding participants younger than 50 years old (n = 132,168), without information on tea or coffee intake (n = 2,074), with prevalent stroke or dementia (n = 2,583), 365,682 participants were ultimately included in the present study to assess associations of coffee and tea with stroke and dementia (). Of 502,507 participants, after excluding participants with no incidence of stroke up to June 31, 2020 (n = 488,581), without information on tea or coffee intake (n = 114), and incident dementia before stroke (n = 460), 13,352 participants were ultimately included in this study to assess the association of coffee and tea with poststroke dementia ().

Of the 365,682 participants, the mean age was 60.4 ± 5.1 years, and 167,060 (45.7%) were males. In total, 75,986 (20.8%) participants were noncoffee drinkers, and 50,009 (13.7%) participants were nontea drinkers. The distribution of the combination of coffee and tea intake is shown in . Of the 365,682 participants, 59,558 (16.29%) participants reported drinking 0.5 to 1 cup of coffee and ≥4 cups of tea per day, accounting for the largest proportion, followed by 50,015 (13.68%) participants reported drinking 0 cup of coffee and ≥4 cups of tea per day; besides, 44,868 (12.27%) participants reported drinking 2 to 3 cups of coffee and 2 to 3 of tea per day. The baseline characteristics of the participants are provided in . Compared to the characteristics of participants who did not drink coffee, coffee drinkers were more likely to be male, white, former smokers, current drinkers, have a university degree, and have a high income. Likewise, as compared to nontea drinkers, tea drinkers were more likely to be males, never smokers, and current drinkers, with a university degree, and high physical activity. Furthermore, compared to participants who drank neither coffee nor tea, those who drank both beverages were more likely to be older adults, males, white, former smokers, current drinkers, have a university degree, and have a high income (). Coffee intake (cups/day) was related to tea intake (r = −0.337, P < 0.001). Both coffee and tea drinking were related to sex, age, ethnicity, qualification, income, BMI, physical activity, alcohol status, smoking status, consumption of sugar-sweetened beverages, LDL, cancer, diabetes, and CAD, but not related to HDL (). During a median follow-up of 11.35 years for new onset disease, 10,053 participants (2.8%) developed stroke (5,630 ischemic strokes and 1,815 hemorrhagic strokes), and 5,079 participants (1.4%) developed dementia (2,128 Alzheimer disease and 1,223 vascular dementia).

Nonlinear association

Restricted cubic spline models were used to evaluate the relationship between coffee, tea, and their combination with stroke, dementia, and poststroke dementia. In both unadjusted () and multiadjusted models (), the combination of coffee and tea was associated with stroke, dementia, and poststroke dementia. In multiadjusted models, the associations of coffee and tea with stroke and dementia were nonlinear (P for nonlinear <0.001), and coffee intake of 2 to 3 cups/d or tea intake of 3 to 5 cups/d separately or both coffee and tea intake of 4 to 6 cups/d were linked with the lowest hazard ratio (HR) of incident stroke and dementia. Besides, the combination of tea and coffee was associated with lower risk of poststroke dementia, with the lowest risk of incident poststroke dementia at a daily consumption level of 3 to 6 cups of coffee and tea (HR, 0.52, 95% CI, 0.32 to 0.83; P = 0.007).

Restricted cubic spline models for the relationship between coffee, tea, and their combination with stroke, dementia, and poststroke dementia.

(A1) Coffee and stroke. (A2) Tea and stroke. (A3) Combination of coffee and tea on stroke. (B1) Coffee and dementia. (B2) Tea and dementia. (B3) Combination of coffee and tea on dementia. (C1) Coffee and poststroke dementia. (C2) Tea and poststroke dementia. (C3) Combination of coffee and tea on poststroke dementia. The 95% CIs of the adjusted HRs are represented by the shaded area. Restricted cubic spline model is adjusted for sex, age, ethnicity, qualification, income, BMI, smoking status, alcohol status, physical activity, diet pattern, consumption of sugar-sweetened beverages, HDL, LDL, cancer, diabetes, CAD, and hypertension, and we adjusted for coffee in tea analysis or for tea in coffee analysis. BMI, body mass index; CAD, cardiovascular arterial disease; HDL, high-density lipoprotein; HR, hazard ratio; LDL, low-density lipoprotein.

Coffee and tea with stroke risk

To analyze the association between coffee and tea intake and new onset outcomes, we defined coffee and tea intake into the following categories: 0, 0.5 to 1, 2 to 3, and ≥4 cups/day. We investigated the association of each coffee and tea intake with stroke and its subtypes (). In unadjusted Cox models, coffee and tea intakes were associated with lower risk of stroke (). After multivariable adjustment, coffee intake was associated with lower risk of stroke. Compared to that of noncoffee drinkers, HRs (95% CI) for coffee intake of 0.5 to 1, 2 to 3, and ≥4 cups/d were 0.90 (95% CI, 0.85 to 0.95; P < 0.001), 0.88 (95% CI, 0.84 to 0.94; P < 0.001), and 0.92 (95% CI, 0.86 to 0.98; P = 0.009), respectively. Likewise, after multivariable adjustment for confounding factors, tea intake was associated with lower risk of stroke. HRs (95% CI) of stroke for tea intake of 0.5 to 1, 2 to 3, and ≥4 cups/d were 0.97 (95% CI, 0.89 to 1.04; P = 0.386), 0.84 (95% CI, 0.79 to 0.90; P < 0.001), and 0.84 (95% CI, 0.79 to 0.90; P < 0.001), respectively. In addition, each coffee and tea were associated with lower risk of ischemic stroke, but not with hemorrhagic stroke (P > 0.05).

Association of coffee and tea intake with stroke and its subtypes.

(A) Coffee and tea with stroke. (B) Coffee and tea with ischemic stroke. (C) Coffee and tea with hemorrhage stroke. Multivariable model is adjusted for sex, age, ethnicity (White, Asian or Asian British, Black or Black British, and Other ethnic group), qualification (college or university degree, A levels/AS levels or equivalent, O levels/GCSEs or equivalent, CSEs or equivalent, NVQ or HND or HNC or equivalent, other professional qualifications, or none of the above), income (less than £18,000, 18,000 to 30,999, 31,000 to 51,999, 52,000 to 100,000, and greater than 100,000), BMI (<25, 25 to <30, 30 to <35, and ≥35 kg/m2), smoking status (never, former, and current), alcohol status (never, former, and current), physical activity (low, moderate, and high), diet pattern (healthy and unhealthy, created by fruits, vegetables, fish, processed meats, unprocessed red meats, whole grains, and refined grains), consumption of sugar-sweetened beverages, HDL, LDL, cancer, diabetes, CAD, and hypertension, and we adjusted for coffee in tea analysis or for tea in coffee analysis. A, Advanced; AS, Advanced Subsidiary; BMI, body mass index; CAD, cardiovascular arterial disease; CSE, Certificate of Secondary Education; GCSE, General Certificate of Secondary Education; HDL, high-density lipoprotein; HNC, Higher National Certificate; HND, Higher National Diploma; HR, hazard ratio; LDL, low-density lipoprotein; NVQ, National Vocational Qualification; O, Ordinary.

Furthermore, we examined the joint association of coffee and tea intake with stroke and its subtypes (). We found that both in unadjusted () and multiadjusted models (), the combination of coffee and tea was associated with lower risk of stroke and ischemic stroke. In multiadjusted models, compared with those who did not drink tea and coffee, HRs of drinking 2 to 3 cups of coffee and 2 to 3 cups of tea per day were 0.68 (95% CI, 0.59 to 0.79; P < 0.001) and 0.62 (95% CI, 0.51 to 0.75; P < 0.001) for stroke and ischemic stroke, respectively. However, no association was observed for coffee and tea with a hemorrhagic stroke. There was a statistical interaction between tea and coffee intake on stroke (P < 0.001).

Coffee and tea with dementia risk

We assessed the association of each coffee and tea with dementia and its subtypes (). In unadjusted Cox models, intake of coffee, tea, and their combination were associated with lower risk of dementia and vascular dementia, but not with Alzheimer disease (). After multivariable adjustment for confounding factors, coffee intake was associated with lower risk of dementia and vascular dementia, but not with Alzheimer disease. Likewise, after multivariable adjustment, tea intake was associated with lower risk of dementia and vascular dementia, but not with Alzheimer disease. Next, we assessed the joint association of coffee and tea intake with dementia and its subtypes. We found that the lowest risk of incident dementia at a daily consumption level of 0.5 to 1 cup of coffee and ≥4 cups of tea. Compared with those who did not drink coffee and tea, HR (95% CI) for drinking 0.5 to 1 cup of coffee and ≥4 cups of tea per day was 0.70 (95% CI, 0.58 to 0.86; P < 0.001), and HR (95% CI) for drinking 2 to 3 cups of coffee and 2 to 3 cups of tea per day was 0.72 (95% CI, 0.59 to 0.89; P = 0.002). There was a statistical interaction between tea and coffee intake on dementia and vascular dementia (P = 0.0127). Furthermore, the combination of coffee and tea intake was associated with lower risk of vascular dementia, but not with Alzheimer disease.

Association of coffee and tea intake with dementia and its subtypes.

(A) Coffee and tea with dementia. (B) Coffee and tea with Alzheimer disease. (C) Coffee and tea with vascular dementia. Multivariable model is adjusted for sex, age, ethnicity (White, Asian or Asian British, Black or Black British, and Other ethnic group), qualification (college or university degree, A levels/AS levels or equivalent, O levels/GCSEs or equivalent, CSEs or equivalent, NVQ or HND or HNC or equivalent, other professional qualifications, or none of the above), income (less than £18,000, 18,000 to 30,999, 31,000 to 51,999, 52,000 to 100,000, and greater than 100,000), BMI (<25, 25 to <30, 30 to <35, and ≥35 kg/m2), smoking status (never, former, and current), alcohol status (never, former, and current), physical activity (low, moderate, and high), diet pattern (healthy and unhealthy, created by fruits, vegetables, fish, processed meats, unprocessed red meats, whole grains, and refined grains), consumption of sugar-sweetened beverages, HDL, LDL, cancer, diabetes, CAD, and hypertension, and we adjusted for coffee in tea analysis or for tea in coffee analysis. A, Advanced; AS, Advanced Subsidiary; BMI, body mass index; CAD, cardiovascular arterial disease; CSE, Certificate of Secondary Education; GCSE, General Certificate of Secondary Education; HDL, high-density lipoprotein; HNC, Higher National Certificate; HND, Higher National Diploma; HR, hazard ratio; LDL, low-density lipoprotein; NVQ, National Vocational Qualification; O, Ordinary.

Additionally, we evaluate the HRs of participants who drank both coffee and tea compared to those who only drank either coffee or tea (). After adjustment for confounders, compared with participants who only drank either coffee or tea, those who drank both coffee and tea was associated with lower risk of stroke (HR, 0.89; 95% CI, 0.86 to 0.93; P < 0.001), ischemic stroke (HR, 0.89; 95% CI, 0.84 to 0.94; P < 0.001), dementia (HR, 0.92; 95% CI, 0.87 to 0.98; P = 0.001), and vascular dementia (HR, 0.82; 95% CI, 0.72 to 0.92; P < 0.001).

Coffee and tea with poststroke dementia risk

We further studied the association of coffee and tea with dementia and its subtypes among participants with stroke (). Of 13,352 participants with stroke, during a median follow-up of 7.07 years, 646 participants (4.8%) developed dementia (119 Alzheimer disease and 315 vascular dementia). In unadjusted Cox models, coffee and the combination of coffee and tea were associated with lower risk of dementia (). After multivariable adjustment, compared with noncoffee drinkers, participants who had a daily consumption level of 2 to 3 cups of coffee were associated with a lower (HR, 0.80; 95% CI, 0.64 to 0.99; P = 0.044) risk of dementia, but not with Alzheimer disease and vascular dementia. In addition, compared to nontea drinking, tea intake was not associated with dementia and its subtypes among participants with stroke. Next, we assessed the combination of coffee and tea intake on dementia and its subtypes among participants with stroke. We found that the combination of coffee and tea was associated with lower risk of poststroke dementia. Compared with those who did not drink coffee and tea, HRs of drinking 0.5 to 1 cup of coffee and 2 to 3 cups of tea per day were 0.50 (95% CI, 0.31 to 0.82; P = 0.006) for poststroke dementia. However, no association was observed between coffee and tea with Alzheimer disease and vascular dementia. There were no interactions between tea and coffee intake on dementia and vascular dementia (P > 0.05).

We also evaluated the associations of coffee types with stroke () and dementia (). Among coffee drinkers, 160,741 (44.0%), 63,363 (17.3%), and 57,397 (15.7%) participants reported drinking instant, ground, and decaffeinated coffee, respectively. In multiadjusted Cox regression models, compared to instant coffee, ground coffee was not associated with stroke (HR, 0.98; 95% CI, 0.93 to 1.04; P = 0.619) and its subtypes. Compared to decaffeinated coffee, instant coffee was not associated with stroke (HR, 0.95; 95% CI, 0.90 to 1.01; P = 0.074) and its subtypes, while ground coffee was associated with a lower risk of stroke (HR, 0.90, 95% CI, 0.84 to 0.97; P = 0.006) and ischemic stroke (HR, 0.90, 95% CI, 0.82 to 1.00; P = 0.045). For dementia, in multiadjusted Cox regression models, compared to instant coffee, ground coffee was associated with a lower risk of dementia (HR, 0.83; 95% CI, 0.77 to 0.89; P < 0.001), Alzheimer disease (HR, 0.77; 95% CI, 0.69 to 0.87; P < 0.001), and vascular dementia (HR, 0.82; 95% CI, 0.70 to 0.96; P = 0.012). Compared to decaffeinated coffee, instant coffee was associated with lower risk of dementia (HR, 0.85; 95% CI, 0.79 to 0.92; P < 0.001), Alzheimer disease (HR, 0.81; 95% CI, 0.72 to 0.91; P < 0.001), and vascular dementia (HR, 0.84; 95% CI, 0.72 to 0.99; P = 0.036); ground coffee was associated with lower risk of dementia (HR, 0.74; 95% CI, 0.66 to 0.82; P < 0.001), Alzheimer disease (HR, 0.67; 95% CI, 0.57 to 0.78; P < 0.001), and vascular dementia (HR, 0.74; 95% CI, 0.59 to 0.92; P = 0.008).

Sensitivity analyses

When analyses were stratified by age, the association between the combination of coffee and tea and the risk of stroke was more pronounced in individuals aged 50 to 65 years old (P for interaction = 0.044; ), but not dementia (P for interaction = 0.091; ). Associations for coffee/tea intake with incident stroke and dementia did not meaningfully differ by sex (), smoking status (), alcohol status (), physical activity (), BMI (), and diet pattern () (all P for interaction >0.05). The results were not much altered compared with those from initial analyses when we repeated analyses: (1) excluding participants with incident stroke or dementia during the first 2 years of follow-up (); (2) excluding participants with major prior diseases (e.g., cancer, coronary artery disease, and diabetes) at baseline (); (3) including participants younger than 50 years old (); (4) with additional more detail adjustment for smoking and alcohol statuses (); and (4) using a competing risk regression model ().

Discussion

In this large prospective cohort study, we found that (1) the separate and combined intake of tea and coffee were associated with lower risk of stroke, ischemic stroke, dementia, and vascular dementia; (2) participants who reported drinking 2 to 3 cups of coffee with 2 to 3 cups of tea per day were associated with about 30% lower risk of stroke and dementia; (3) the combination of coffee and tea seemed to correlate with lower risk of stroke and dementia compared to coffee or tea separately; and (4) intake of coffee alone or in combination with tea was associated with lower risk of poststroke dementia.

Many studies have investigated the relationship between separate coffee and tea consumption and stroke, but with inconsistent findings. Some reported inverse associations [37,38], while others revealed positive or null connections [16,28,39-41]. Our findings supported that tea and coffee consumption related to lower risk of stroke, in accord with a review that summarized available evidence from experimental studies, prospective studies, and meta-analyses reported that tea and coffee consumption might relate to lower risk of stroke [41]. The current study also found a stronger association between the combination of tea and coffee and ischemic stroke compared to hemorrhagic stroke. Studies have reported that coffee and tea may have a different impact upon different subtypes of stroke due to the different pathogenesis and pathophysiology of the subtypes of stroke [42,43]. A possible mechanism for this relationship is that coffee and tea are inversely associated with endothelial dysfunction, which is a major cause of ischemic stroke [44-47]. Another potential mechanism may be that coffee contains caffeine and is a rich source of antioxidants, and evidence demonstrated that coffee was inversely associated with cardiometabolic risk, including cardiovascular disease (CVD), type 2 diabetes, lipids, and hypertension [25,48,49]. Although these explanations are biologically plausible, further studies are warranted to provide the exact underlying mechanisms of coffee and tea intake in developing ischemic stroke.

The association of a combination of coffee and tea on stroke was supported by a previous study. Kokubo and colleagues conducted a prospective study, including 82,369 Japanese individuals, aged 45 to 74 years, which found that higher green tea or coffee consumption was associated with a lower risk of CVD and stroke subtypes (especially in intracerebral hemorrhage) [16]. The difference is that our findings suggested that coffee and tea intake were associated with ischemic stroke rather than hemorrhagic stroke. The cause of this difference might be the study design, ethnic background, and classification of tea consumption. Further experimental studies are needed to verify our findings. In addition, Gelber and colleagues conducted the Honolulu-Asia Aging Study including 3,494 men, which found that coffee and caffeine intake in midlife was not associated with overall dementia, Alzheimer disease, vascular dementia, or cognitive impairment [22], which is inconsistent with our findings. The cause of this difference might be the sample size.

Our study showed that there was an interaction between coffee and tea that associated with stroke and dementia. There are several mechanisms whereby the combination of coffee and tea may be related to stroke and dementia. First, coffee is the primary source of caffeine and contains phenolics and other bioactive compounds with potential beneficial health effects. Likewise, tea contains caffeine, catechin polyphenols, and flavonoids, which have been reported to have neuroprotective roles such as antioxidative stress, anti-inflammation, inhibition of amyloid-beta aggregation, and antiapoptosis [18,50,51]. Coffee and tea are distinct beverages with both overlapping and different contents [14]. One potential mechanism may be related to the combined protective role of the different antioxidant and other biological contents in these 2 beverages [16]. Second, coffee and tea have a specific polyphenolic content, characterized by hydroxycinnamic acids in the former, and catechins in the latter, which have demonstrated potential benefits in ameliorating endothelial function, insulin resistance, and anti-inflammation, and have different target molecules [52]; thereby, the specific polyphenolic contents of coffee and tea may play a combined protective role in the pathogenesis of stroke and dementia. Third, both coffee and tea were related to lower cardiometabolic risks, including type 2 diabetes, hypertension, and CAD [25,48,49]. Thus, consuming the 2 beverages in combination may have a joint health benefit for preventing the risk of stroke and dementia. Fourth, the interaction between coffee and tea drinking for both stroke and dementia may have arisen due to chance. Finally, consumption of coffee and tea may jointly modulate certain cytokine activation [53-55]. Further validation in animal experiments is warranted to examine coffee and tea’s potential joint associations on dementia.

Strengths of this study include its large sample size of UK Biobank participants, the prospective design, and long-time follow up. Our present study also had several limitations. First, coffee and tea intakes were self-report at baseline, which may not reflect long-term consumption patterns. Potential changes in coffee and tea consumptions after the baseline examination may have influenced our risk estimates. Future research is needed to investigate the impact of changes in coffee and tea intake over time on stroke and dementia risk. Second, coffee and tea intakes are all self-reported measures, which could lead to inaccurate responses, although most large epidemiological studies rely on self-reported questionnaires. Third, people who volunteer for the UK Biobank cohort tend to be, on average, more health conscious than nonparticipants, which may lead to underestimation prevalence and incidence of stroke and dementia [56]. Fry and colleagues reported that UK Biobank participants generally live in less socioeconomically deprived areas; are less likely to be obese, to smoke, and to drink alcohol; and have fewer self-reported health conditions, with evidence of a “healthy volunteer” selection bias [56]. Fourth, similar to most observational studies, the bias that may be caused by unmeasured confounding factors remains (e.g., mental disease, sleep pattern, and genetic predisposition), even though multiple sensitivity analyses have been carried out in the current study. Furthermore, given the low absolute proportions of participants who developed the primary events, there is likely to be residual confounding based on the baseline demographics and risk factors, as well as the unmeasured confounding on healthy lifestyle that could more likely occur in some types of tea and coffee drinkers. Thus, the conclusions could be tempered by the low absolute risk and the likely residual confounding. Finally, since most of the UK Biobank participants were of white British (96%), our findings may only be generalizable to demographically similar cohorts, and this limitation precludes the generalization of these findings to the general population.

Among neurological disorders, stroke (42%) and dementia (10%) dominate [10]. Strokes can lead to cognitive impairment and even lead to poststroke dementia. In addition, covert stroke and silent brain ischemia contribute to cognitive impairment and dementia [10]. Hence, preventing the risk of stroke and dementia is particularly important. Despite advances in understanding the pathophysiology of stroke and dementia, clinical treatment of stroke and dementia continues to be suboptimal. Therefore, identifying the preventable risk factors for stroke and dementia is of high priority. Our findings raise the possibility of a potentially beneficial association between moderate coffee and tea consumption and risk of stroke and dementia, although this study cannot establish a causal relationship. Lifestyle interventions, including promotion of healthy dietary intake (e.g., moderate coffee and tea consumption), might benefit older adults by improving stroke as well as subsequent dementia. From a public health perspective, because regular tea and coffee drinkers comprise such a large proportion of the population and because these beverages tend to be consumed habitually throughout adult life, even small potential health benefits or risks associated with tea and coffee intake may have important public health implications. Further clinical trials on lifestyle interventions will be necessary to assess whether the observed associations are causal.

Conclusions

In conclusion, we found that drinking coffee and tea separately or in combination were associated with lower risk of stroke and dementia. Moreover, drinking coffee alone or in combination with tea was associated with lower risk of poststroke dementia. Our findings support an association between moderate coffee and tea consumption and risk of stroke and dementia. However, whether the provision of such information can improve stroke and dementia outcomes remains to be determined.

STROBE Checklist.

STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

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Analysis plan.

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Diet component definitions used in the UK Biobank study.

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Detailed information on missing covariates.

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Baseline characteristics by the combination of coffee and tea intake in the UK Biobank cohort.

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Correlation between coffee and tea intake and other covariates.

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Association of coffee and tea with stroke in the UK Biobank cohort (unadjusted models).

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Association of coffee and tea with dementia in the UK Biobank cohort (unadjusted model).

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HRs of stroke and dementia for participants who drank both coffee and tea compared to those who only drank either coffee or tea.

HR, hazard ratio.

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Association of coffee and tea with poststroke dementia in the UK Biobank cohort (unadjusted models).

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Risk of incident stroke according to coffee types in the UK Biobank.

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Risk of incident dementia according to coffee types in the UK Biobank.

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Association of coffee and tea with stroke in the UK Biobank cohort by age.

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Association of coffee and tea with dementia in the UK Biobank cohort by age.

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Association of coffee and tea with stroke in the UK Biobank cohort by sex.

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Association of coffee and tea with dementia in the UK Biobank cohort by sex.

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Association of coffee and tea with stroke in the UK Biobank cohort by smoking status.

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Association of coffee and tea with dementia in the UK Biobank cohort by smoking status.

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Association of coffee and tea with stroke in the UK Biobank cohort by alcohol status.

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Association of coffee and tea with dementia in the UK Biobank cohort by alcohol status.

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Association of coffee and tea with stroke in the UK Biobank cohort by physical activity.

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Association of coffee and tea with dementia in the UK Biobank cohort by physical activity.

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Association of coffee and tea with stroke in the UK Biobank cohort by BMI.

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Association of coffee and tea with dementia in the UK Biobank cohort by BMI.

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Association of coffee and tea with stroke in the UK Biobank cohort by diet pattern.

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Association of coffee and tea with dementia in the UK Biobank cohort by diet pattern.

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Association of coffee and tea with stroke after exclusion of stroke occurring during the first 2 years of follow-up in the UK Biobank cohort.

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Association of coffee and tea with dementia after exclusion of dementia occurring during the first 2 years of follow-up in the UK Biobank cohort.

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Association of coffee and tea with stroke after exclusion of individuals with major prior diseases in the UK Biobank cohort.

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Association of coffee and tea with dementia after exclusion of individuals with major prior diseases in the UK Biobank cohort.

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Association of coffee and tea with stroke in the UK Biobank cohort (including participants younger than 50 years old).

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Association of coffee and tea with dementia in the UK Biobank cohort (including participants younger than 50 years old).

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Association of coffee and tea with stroke in the UK Biobank cohort (detail adjusting for smoking and alcohol statuses).

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Association of coffee and tea with dementia in the UK Biobank cohort (detail adjusting for smoking and alcohol statuses).

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Association of coffee and tea with stroke in the UK Biobank cohort: Results from competing risk regression models.

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Association of coffee and tea with dementia in the UK Biobank cohort: Results from competing risk regression models.

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Flowchart of participant selection.

(A) Association of coffee and tea with stroke and dementia. (B) Association of coffee and tea with poststroke dementia.

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The distribution of combination of coffee and tea intake.

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Unadjusted restricted cubic spline models for the relationship between coffee, tea, and their combination with stroke, dementia, and poststroke dementia.

(A1) Coffee and stroke. (A2) Tea and stroke. (A3) Combination of coffee and tea on stroke. (B1) Coffee and dementia. (B2) Tea and dementia. (B3) Combination of coffee and tea on dementia. (C1) Coffee and poststroke dementia. (C2) Tea and poststroke dementia. (C3) Combination of coffee and tea on poststroke dementia. The 95% CIs of the adjusted HRs are represented by the shaded area. HR, hazard ratio.

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Association of coffee and tea intake with dementia among participants with stroke.

Note: Multivariable model is adjusted for sex, age, ethnicity (White, Asian or Asian British, Black or Black British, and Other ethnic group), qualification (college or university degree, A levels/AS levels or equivalent, O levels/GCSEs or equivalent, CSEs or equivalent, NVQ or HND or HNC or equivalent, other professional qualifications, or none of the above), income (less than £18,000, 18,000 to 30,999, 31,000 to 51,999, 52,000 to 100,000, and greater than 100,000), BMI (<25, 25 to <30, 30 to <35, and ≥35 kg/m2), smoking status (never, former, and current), alcohol status (never, former, and current), physical activity (low, moderate, and high), diet pattern (health and unhealth, created by fruits, vegetables, fish, processed meats, unprocessed red meats, whole grains, and refined grains), consumption of sugar-sweetened beverages, HDL, LDL, cancer, diabetes, CAD, and hypertension, and we adjusted for coffee in tea analysis or for tea in coffee analysis. A, Advanced; AS, Advanced Subsidiary; BMI, body mass index; CAD, cardiovascular arterial disease; CSE, Certificate of Secondary Education; GCSE, General Certificate of Secondary Education; HDL, high-density lipoprotein; HNC, Higher National Certificate; HND, Higher National Diploma; HR, hazard ratio; LDL, low-density lipoprotein; NVQ, National Vocational Qualification; O, Ordinary.

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11 Feb 2021

Dear Dr Wang,

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9 Jul 2021

Dear Dr. Wang,

Thank you very much for submitting your manuscript "Association of coffee and tea with the risk of developing stroke, dementia, and post-stroke dementia" (PMEDICINE-D-21-00534R1) for consideration at PLOS Medicine.

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Requests from the editors:

1. Title: Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

2. Interpretations and causal language: In the Abstract (and throughout manuscript,including the Author Summary): Please avoid the use of language that implies causality. For example at line 23-24 please revise: “...the separate and combined effects of coffee and tea on the risk of developing stroke, dementia, and post-stroke dementia…” and at line 41 and in the Conclusions, please avoid: “...reduced the risk…” and similar language. Throughout, we suggest referring to associations, and we recommend interpreting the results without overreaching what can be concluded from the data.

3. Abstract: Please quantify all main results described with both 95% CIs and p values, mentioning any dependent variables that are adjusted for in the analyses.

4. Abstract: In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

5. In-text references: For in-text references within brackets, please add a space between the preceding word and the bracket.

6. Methods: Line 144: Please check if this should be “tea” rather than “coffee”

7. Methods: Line 163: Please provide some rationale/description of the selection of covariates.

8. Methods: Line 173-174: Please provide some information about the classification into “healthy” vs. “unhealthy” diet pattern (you could refer to Table S1).

9. Methods: Line 180: Please clarify the sentence: “Restricted Cubic Spline modeling of the relationship between coffee, tea, and their combination with stroke, dementia, and post-stroke dementia.”

10. Methods: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

11. Methods: Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

12. Results: Please provide 95% CIs and p values for all main analyses presented in the text.

13. Results: Line please provide both unadjusted as well as adjusted results (at least in tables if not presented in the text).

14. Results: Line 244: It may be helpful to indicate within Figure 1, or in a separate table, the p values for relationships in the Restricted Cubic Spline modeling analyses.

15. Results: Line 244-253: In the paragraph describing associations between coffee/tea consumption and stroke, please rephrase “...the combination of tea and coffee could reduce the risk of post-stroke dementia…” and similar statements, to avoid implying causality.

16. Discussion: Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

17. Discussion: In the first paragraph and throughout, please avoid statements that imply causality, such as “...the separate and combination of tea and coffee could significantly reduce the risk of stroke…” and please address the study implications without overreaching what can be concluded from the data.

18. Discussion: Line 334: Please format the in-text citation for reference 20 within brackets.

19. Discussion: Line 389-391: Please clarify what is meant by “...due to the restrictions on people’s health consciousness and regional medical level, stroke and dementia prevalence was far greater than collected” in the discussion of the study limitations.

20. Table 1: Please include definitions for all abbreviations used in the legend. Please clarify if any statistical tests were used to compare baseline characteristics.

21. Figure 1: If possible, please also provide the unadjusted model results.

22. Figure 2, 3, 4: Please also provide the results from the unadjusted models.

23. Table S2, S3 : Please provide p values in addition to the 95% CIs, and please provide the unadjusted results.

24. Table S4, S5, S6, S7 : Please also include the unadjusted results.

Comments from the reviewers:

Reviewer #1: This is an interesting topic that is well suited for study in the UK Biobank cohort. However, the authors did not provide strong scientific rationale for studying a potential synergistic interaction between coffee and tea with risk of stroke, dementia, and post-stroke dementia, and the conclusions, including potential implications for clinical practice, were strong given the observational nature of the study and the lack of rationale/outside evidence supporting a potential causal interaction. Greater caution is warranted in making causal inferences from an observational study.

Major comments for the authors consideration:

* In the introduction it is important to state what the rationale is for undertaking an interaction analysis for coffee and tea and the outcomes. To simply state that both exposures may impact the outcome(s) is relatively uninteresting. What is the hypothesized scale (i.e., additive, multiplicative, both) and why?

* The authors' motivation for studying coffee and tea with post-stroke dementia is also not made clear in the introduction.

* While the study was limited to coffee and tea assessed at baseline, it would be important to address how these exposures change over time in the cohort and discuss how such might bias the results. The UK Biobank has serial dietary assessments on subsets of participants. Did the authors consider using this data to explore how coffee and tea drinking changed among this subset of participants? Although numbers are likely small, it would be particularly interesting if they were able to see if these behaviors changed at a similar of different rate to those who did or did not have a stroke.

* The nonlinear associations illustrated in Figure 1 suggest that HRs increase at higher levels of intake. Given the large size of the cohort, continuous measurement of coffee and tea, and indication of nonlinear associations, why did the authors define the highest category of intake as 4+ cups/day?

* Prior UKBB analyses of coffee and/or tea have indicated that these exposures may be confounders of each other. Did the authors run analyses adjusting for coffee in tea analyses or for tea in coffee analyses to explore this possibility?

* Broadly adjusting for smoking and alcohol drinking status may not be sufficient given that these behaviors are highly correlated with coffee and tea drinking and likely associated with the outcomes of interest. Did the authors consider more detailed adjustment for smoking (e.g., intensity, time since quitting, use of other tobacco products, etc.), or alcohol (e.g., consumption level among current drinkers)? Did any of the covariates included in the models meaningfully alter HRs? If so, which ones and how was this assessed? If not, why? Finally, could CVD-related covariates (e.g., hypertension) be considered mediators? What impact if any did adjusting for these covariates have?

* How were disease history variables defined?

* Authors should refrain from using causal language throughout the paper (e.g., lines 74-75, line 383).

* In the discussion, the argument for why there could be a causal interaction is weak, while little may be known about the combined effects of coffee and tea drinking, the biological plausibility for a joint effect should be clearly laid out. Currently, it reads as though coffee and tea contain the same beneficial compounds (e.g., caffeine, polyphenols, etc.) and so more of either or both is beneficial. Thus, the case for prescriptions, citing the best combination of coffee and tea, seems unfounded and potentially misleading.

* Line 392, although some types of coffee preparations were not assessed in the cohort the two main types of coffee (i.e., instant and ground) were. Did the authors consider associations with instant versus brewed coffee? What about caffeinated versus decaffeinated?

Minor comments:

* The paper is generally very well written with the exception of the discussion, which is confusing and would benefit from proof-reading (some examples below).

* Citation for line 95-96 "In principle, 90% of strokes and 35% of dementia have been

estimated to be preventable."

* The following sentence should be revised so that it doesn't start with a number or use the phrase "were daily drinking": "59,558 (16.29%) participants reported drinking 0.5-1 cup of coffee and ≥4 cups of tea per day.."

* Line 334- Fix citation to match formatting throughout.

* "While Qian et al.[24] reported that coffee consumption is not causally associated with the risk of stroke, which is different from ours results." The results from the current study should also not be interpreted as causal, please rephrase.

* Line 337- and coffee intake "groupings" is probably critical

* Line 339- compared to hemorrhagic stroke

* The association of combination of coffee and tea on stroke was supporting supported by a previous study

* Line 349- that included "82,369" Japanese, age aged

* Line 351- The "difference" is that our

* Line 357-358 reword, unclear- While this study mainly focuses on caffeine intake, but not different combinations of coffee and tea intake.

* Line 360- Not clear "an interaction effect for each other?"

* Line 369- Needs citation "Consumption of coffee and tea may jointly modulate certain cytokine activation."

* Line 373- Needs citation- Among neurological disorders, stroke (42%) and dementia (10%) dominate.

Reviewer #2: This is an interesting and useful study on the association of coffee and tea with the risk of developing stroke, dementia, and post-stroke dementia. However, there are a few major issues needing attention.

1) Competing risk. In Cox models, when the oucome is an incident disease (stroke, demintia and etc) other than all-cause mortality, models taking into account of competing risk should be used. However, competing risk was not considered at all in the paper which is not adequate.

2) The dose-response relationships in Figure 1 is simply univariate relationship which's not multiple-adjusted by confounders so could be misleading therefore can't interpret too much.

3) The data on coffee and tea intake at baseline doesn't have information as how long they have been drinking and whether they are frequent drinkers of coffee or tea. This will have a big impact of the validity of causal relationship between coffee/tea and stroke/dementia.

4) Association is not causation. So far what authors found is association between coffee/tea and stroke/dementia, but strong causal relationship was concluded throughout the paper, for example in abstract, "We found that drinking coffee and tea separately or in combination could reduce the risk of stroke and dementia. Additionally, the combination of tea and coffee could reduce the risk of post-stroke dementia". This's a very strong claim which is not adequate. Authors should really tone down the claims.

5) The key message was still not clearly expressed. We know the impact of coffee or tea separately on stroke and dementia, but what exactly is the combined impact? what's the difference compared to individula effect? larger, smaller or the same? and what's possible explanations of findings for the combined effect?

Reviewer #3: In this study, Zhang et al examined associations of coffee and tea with the risk of developing stroke, dementia, and post-stroke dementia among 365,682 participants in the UK Biobank. The authors found that drinking coffee and tea separately or in combination was associated with lower risks of stroke and dementia, particularly vascular dementia. This is a highly interesting study, especially the finding that intakes of coffee and tea were associated with lower risk of vascular dementia, but not Alzheimer disease, which provides further evidence that coffee intake is related to cardiometabolic health.

Main questions

1) Figure 4 is unnecessary. Based on figures 1-3, coffee or tea is likely to be related to risks of dementia through stroke. If the analysis is restricted to stroke participants, it is expected that coffee/tea is not related to dementia or vascular dementia due to block of the mediator (stroke). I do not think figure 4 is needed. Additionally, it is strange that coffee or tea separately is not associated with dementia, but jointly associated with a lower risk. Might need to double check the data analysis procedures.

2) Instead of figure 4, would it be possible to look at coffee and tea intake after development of stroke with development of dementia? Line 382. "Our findings highlight the potential benefits of coffee and tea consumption to reduce the risk of dementia in participants with stroke". This statement is not convincingly supported by the data, unless you can show an inverse association for coffee/tea intake after stroke incidence. However, I think this study showed potential benefits of coffee and tea in preventing vascular dementia.

3) To show the robustness of the findings, the author can conduct stratified analysis by smoking status, which is related to coffee intake, as well as age, sex, physical activity, BMI, diet quality, and alcohol intake.

4) "For covariate information was missing (<20%), we used multiple imputations". Can you provide a table on missing rate of covariates? How many covariates were conducted multiple imputations?

5) "After excluding participants younger than 50 years old (n =132,168)", Why these participants were excluded from the study? They should be included.

6) In line 343, endothelial dysfunction is discussed as a potential mechanism linking coffee/tea intake with risk of stroke. Coffee also have anti-oxidant effect and is related to lower cardiometabolic risk, including lipids, type 2 diabetes, and CVD. These should be discussed as well.

7) In addition, Gelber et al. reported that coffee and caffeine intake in midlife was not associated with cognitive impairment, dementia, and its subtypes. Would the inconsistency in the findings due to sample size?

Minor questions

1) In figure 1, stroke-dementia is confusing.

2) In figures 2-4, the 95% CI were not fully shown for some categories due to the narrow range of x-axis.

3) In figures 2-4, please report number of cases and total participants within each category.

Reviewer #4: In this manuscript, the authors examine the association of coffee and tea intake with risk of developing stroke, dementia, and post stroke dementia in the large UK biobank study.

The manuscript has a number of strengths including very large size and a prospective design. Limitations are appropriately described in the discussion and include assessment of coffee and tea by self-report and likely under-ascertainment of stroke and dementia.

I have a number of comments.

1. The a priori rationale for looking at joint categories of coffee and tea intake is not adequately described or justified. Coffee and tea are distinct beverages with both overlapping and different constituents. Looking through the tables, it looks to me that both coffee and tea intake are associated with these outcomes and I am not convinced that examining joint categories of coffee and tea intake provides much additional insight beyond examining each beverage individually, and furthermore that any differences should not be interpreted as a result of chance.

2. Coffee and tea intake have been reported to be inversely associated with each other in the cohort (and by the way tea should be added to the coffee stratification in table 1; and coffee to the tea stratum). Also, the correlation between coffee and tea intake in the cohort should be described in the top paragraph of page 12, along with the other factors.

It seems possible that cohort members who drink both coffee and tea may differ from non-drinkers of both beverages, as well as exclusive users of either beverage. A table showing baseline characteristics of cohort members who drink both coffee and tea would be a useful addition.

3. As described in Supplementary Figure S2, only a very small proportion of the cohort drinks neither coffee or tea (well under 5%). Yet, this is used as the reference group for the joint categories of coffee and tea. How many participants in this group? I think it would be useful for the authors to provide the number of participants and events in the figures so that readers can evaluate the stability of these estimates.

4. Coffee intake and to some extent tea intake seems to be associated with smoking and alcohol intake. It looks like the authors used relatively broad three-level categories to adjust for potential confounding by each of these exposures. It would be better for the authors to more comprehensively adjust for these important potential confounders. Additionally, the manuscript would benefit from adding in stratified analysis whereby readers can view the associations by stratum of smoking status and alcohol intake.

5. The authors mention the Qian study (24) on page 16 and mention that coffee was not causally related to stroke. However, this analysis uses a mendelian randomization approach which has some strong assumptions. If mentioned, the authors should provide further information about this study including how mendelian randomization approaches may or may not complement more traditional observational epidemiology.

6. The authors mention that they lacked information about how coffee was prepared. However, prior studies in the UK Biobank have indicated that there is some data about preparation, including that most of the consumption was instant coffee. https://biobank.ndph.ox.ac.uk/showcase/field.cgi?id=1508

7. Additionally, the authors mention that their study included only European individuals and so lack of generalization to other groups is a limitation. Yet, in table 1, non-white groups are mentioned, although I agree their proportion is low. Th text should be clarified. Other studies from Asia have examined associations with tea and coffee and these endpoints, including Kokubo which is referenced by the authors (21).

Any attachments provided with reviews can be seen via the following link:

[LINK]

15 Aug 2021

Submitted filename: response to editors and reviews.docx

Click here for additional data file.

20 Sep 2021

Dear Dr. Wang,

Thank you very much for re-submitting your manuscript "Association of coffee and tea with the risk of developing stroke, dementia, and post-stroke dementia: A prospective cohort study" (PMEDICINE-D-21-00534R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by three reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

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We look forward to receiving the revised manuscript by Sep 27 2021 11:59PM.

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------------------------------------------------------------

Requests from Editors:

1. From the academic editor: The comments of the third reviewer do not necessarily need to be addressed, but the comments about the limitations section needs to be expanded in both the discussion and the abstract; the section only includes 3 weaknesses and these should be described more in detail and the conclusions should be tempered by the low absolute risk and the likely residual confounding. Given the low absolute proportions of participants who developed the primary events there is likely to be residual confounding based on the baseline demographics and risk factors, as well as the unmeasured confounding on healthy lifestyle that could more likely occur in some types of tea and coffee drinkers.

2. Title: Please revise the title to: “Consumption of coffee and tea and risk of developing stroke, dementia, and poststroke dementia: A cohort study in the UK Biobank”

3. Data availability statement: Please revise slightly to: “Data from the UK Biobank cannot be shared publicly however data are available from the UK Biobank Institutional Data Access / Ethics Committee (contact via http://www.ukbiobank.ac.uk/ or contact by email at access@ukbiobank.ac.uk) for researchers who meet the criteria for access to confidential data.”

4. Abstract: Methods and Findings: Please clarify here to mention you are looking for associations between coffee/tea consumption and stroke “We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs)...”

5. Abstract: Methods and Findings: ”Please change “sugar-sweetened beverages” to “consumption of sugar-sweetened beverages”, if accurate.

6. Abstract: Methods and Findings: Please revise to indicate the direction of the association, for example, was the combination of coffee and tea consumption associated with lower risks?: “Moreover, the combination of coffee and tea consumption was associated with the risks of ischemic stroke and vascular dementia. Additionally, the combination of tea and coffee was associated with post-stroke dementia, with the lowest risk of incident post-stroke dementia at a daily consumption level of 3-6 cups of coffee and tea (HR, 0.52, 95% CI, 0.32-0.83; P

=0.007).”

7. Abstract: Methods and Findings: In the final limitations sentence, please expand the discussion of the main limitations of the study, as pointed out by the reviewer and academic editor.

8. Abstract: Conclusions: Please indicate the direction of the associations in the conclusions.

9. Author summary: What did the researchers do and find? We suggest revising the first bullet point to: “This study included 365,682 participants (50–74 years old) from the UK Biobank who reported their coffee and tea consumption.” or similar.

We suggest revising the third bullet point to: “Drinking 2–3 cups of coffee with 2–3 cups of tea daily was associated with a 32% lower risk of stroke and a 28% lower risk of dementia”

10. Author summary: What do these findings mean?: We suggest revising the final bullet point to: “These findings may be of interest to clinicians involved in the prevention and treatment of stroke, dementia, and post-stroke dementia”

11. Introduction: Please revise “Coffee is closely related to tea consumption” to read “Coffee consumption is closely related…” if accurate.

12. Introduction: Please clarify what is meant, or revise to: “Coffee and tea are distinct beverages with overlapping components, such as caffeine, and different biologically active constituents, including epigallocatechin gallate and chlorogenic acid [21].” or similar.

13. Methods: Please revise to “The analysis plan was drafted prospectively in February 2020 (S1 Text).” if this is accurate.

14. Methods: Please clarify the six mutually exclusive responses for types of coffee because it is not clear how the responses listed here correspond with six possibilities: ( “...instructed to select one of six mutually exclusive responses, as follows: “Decaffeinated coffee (any type)”, “Instant coffee”, or “Ground coffee (include espresso and filtered coffee).” For tea, please note if any information on “type of tea” was collected after the number of cups per day.

15. Methods: In the covariates section, please revise to “consumption of sugar-sweetened beverages” if accurate. Please revise diet pattern to read “healthy and unhealthy” if this is intended.

16. Results: Please change “sugar-sweetened beverages” to “consumption of sugar-sweetened beverages” in this section, if accurate.

17. Results: When reporting the associations between coffee/tea intake and stroke/dementia, please mention the direction (higher risk or lower risk) where the association is mentioned (e.g. “coffee intake was associated with stroke”).

18. Results: “Next, we assessed the combination of coffee and tea intake on dementia and its subtypes among participants with stroke. We found that the lowest risk of incident dementia was at a daily consumption level of 2–3 cups of coffee and 0 cup of tea.” Please clarify here how this differs from the independent coffee/tea analysis indicating that among coffee drinkers, 2-3 cups of coffee consumed daily was associated with lower risk of dementia, but that no association was identified for tea consumed.

19. Results: Please clarify the results for “Similar results were obtained when we performed stratified analysis by sex (S13-S14 Tables), smoking status (S15-S16 Tables), alcohol status

(S17-S18 Tables), physical activity (S19-S20 Tables), BMI (S21-S22 Tables), and diet pattern (S23-S24 Tables).” It is not clear what the result are being compared to when described as similar.

20. Discussion: Please revise to “...the separate and combined intake of tea and coffee…”

21. Discussion: The example pointed out in the Results (see point #18 above) does not seem to illustrate point 4 from the introductory paragraph (that combination of coffee and tea was associated with post-stroke dementia.) Please clarify this here as well as in the Conclusion paragraph.

22. Discussion: Please revise this sentence (please avoid the word “preventing”) to avoid implying causality: “Our study showed that there was an interaction between coffee and tea in preventing stroke and dementia”

23. Discussion: Please revise this sentence to avoid causal implications. “Our findings highlight the potential benefits of moderate coffee and tea consumption in preventing the risk of stroke and dementia” we instead suggest something such as “Our findings support a potentially beneficial association between moderate coffee and tea consumption and risk of stroke and dementia.”

24. Conclusions: Please note the direction of the relationship between coffee/tea consumption and risk of stroke and dementia. Please revise “Our findings highlight the potential benefits of moderate coffee and tea consumption in preventing stroke and dementia.” to avoid causal implications of the study.

25. Funding, Conflict of Interest, Data availability, Contributions: Please remove these sections from the main text of the manuscript and ensure all relevant information is included with the manuscript submission system metadata.

26. Supporting information file: Throughout, please change the red text to black text. Please avoid the use of bold type in the tables or legends unless the reason for this is made clear. Rather than “former smokers quitted” we suggest “former smokers who have quit” or similar.

27. Supporting information file: Table S2: Please change the text color to black. Please clarify if the N represents number of missing responses. Please define the abbreviations used in the legend.

Comments from Reviewers:

Reviewer #2: Many thanks authors for their great effort to improve the manuscript. All my concerns and comments were professionally addressed by the authors. I am satisfied with the response and revision. Only one very mionr point, it says in the conclusions of the abstract: "We found that drinking coffee and tea separately or in combination were associated with the risk of stroke and dementia. Additionally, the combination of tea and coffee was associated with the risk of post-stroke dementia". I can appreciate authors have toned down all the findings into associations which is adequate. However, it should be fine and clearer to say 'associated with lower risk of' instead of 'associated with the risk of' so that readers will know clearly the direction of the associations. This also applies to the whole paper. Just need to agree with the editor and no need to come back to me again. Thanks.

Reviewer #3: The authors have fully addressed my comments.

Reviewer #4: The authors have thoroughly responded to the reviewer and editor comments and I believe have improved the manuscript. I have one remaining comment: I appreciate the straightforward conclusion of the abstract, that drinking coffee and tea separately, and in combination, was associated with lower risk of stroke and dementia. However, I am skeptical that some specified combination of tea and coffee intake truly yields the strongest association. And although the authors note a statistical interaction between coffee and tea drinking for both stroke and dementia, there doesn't seem to be any clear pattern across any of the strata.

For this reason, I think that the extensive presentation of coffee and tea interaction categories in the abstract distracts from the paper. I suggest they should be removed. I also think that chance should be mentioned as a possible explanation for the interaction on page 24 of the discussion.

Any attachments provided with reviews can be seen via the following link:

[LINK]

26 Sep 2021

Submitted filename: Response to editors and reviewers-R2.doc

Click here for additional data file.

30 Sep 2021

Dear Dr Wang,

On behalf of my colleagues and the Academic Editor, Joshua Willey, I am pleased to inform you that we have agreed to publish your manuscript "Consumption of coffee and tea and risk of developing stroke, dementia, and poststroke dementia: A cohort study in the UK Biobank" (PMEDICINE-D-21-00534R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

Please also address the following editorial requests:

1. Abstract: Please revise the final sentence of the Methods and Findings section to read: "The main limitations were that coffee and tea intake was self-reported at baseline, and may not reflect long-term consumption patterns, unmeasured confounders in observational studies may result in biased effect estimates, and UK Biobank participants are not representative of the whole UK population."

2. Author summary: Under "What do these findings mean?" please revise the first bullet point to: "These findings highlight a potential beneficial relationship between coffee and tea consumption and risk of stroke, dementia, and post-stroke dementia, although causality cannot be inferred."

3. Results, Page 16: There is a typo in the category reported. Please revise to "...44,868 (12.27%) participants reported drinking 2-3 cup of coffee and 2-3 of tea per day..."

4. Results: Page 16: In this same paragraph, please change "whites" to "white" where describing demographics.

5. Discussion: Page 23: Please revise this sentence to: "Kokubo et al. conducted a prospective study included 82369 Japanese individuals, aged 45–74 years..."

6. Discussion: Page 24: Please revise this sentence to: "The difference is that our findings suggested that coffee and tea intake were associated with ischemic stroke rather than hemorrhagic stroke."

7. Discussion: Page 27: Please revise this sentence to: "Our findings raise the possibility of a potentially beneficial association between moderate coffee and tea consumption and risk of stroke and dementia, although this study cannot establish a causal relationship."

8. Conclusions: Page 27: Please revise this sentence to: "Our findings support an association between moderate coffee and tea consumption and risk of stroke and dementia."

PRESS

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Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

Table 1

Baseline characteristics by coffee and tea intake in the UK Biobank cohort.

	Coffee intake, cups/day, No. (%)				Tea intake, cups/day, No. (%)
Characteristic	0	0.5 to 1	2 to 3	≥4	0	0.5 to 1	2 to 3	≥4
No. (%)	75,986 (20.78)	102,404 (28.00)	116,844 (31.95)	70,448 (19.26)	50,009 (13.68)	39,311 (10.75)	107,931 (29.51)	168,431 (46.06)
Age, mean (SD), y	59.99 (5.25)	60.71 (5.16)	60.71 (5.12)	60.17 (5.14)	60.04 (5.16)	60.18 (5.21)	60.59 (5.17)	60.55 (5.15)
Sex, male	32,568 (42.86)	44,785 (43.73)	54,281 (46.46)	35,426 (50.29)	21,436 (42.86)	18,715 (47.61)	49,676 (46.03)	77,233 (45.85)
Coffee intake, mean (SD)	0	0.87 (0.22)	2.39 (0.49)	5.20 (1.59)	3.53 (2.49)	2.83 (2.01)	2.00 (1.61)	1.37 (1.59)
Tea intake, mean (SD)	4.60 (2.77)	4.10 (2.34)	3.02 (2.22)	2.03 (2.42)	0	0.87 (0.22)	2.52 (0.50)	5.69 (1.91)
HDL, mean (SD), mmol/L	1.43 (0.38)	1.48 (0.39)	1.48 (0.39)	1.43 (0.38)	1.45 (0.39)	1.47 (0.39)	1.48 (0.39)	1.46 (0.39)
LDL, mean (SD), mmol/L	3.53 (0.89)	3.59 (0.88)	3.63 (0.88)	3.64 (0.90)	3.63 (0.92)	3.62 (0.89)	3.61 (0.88)	3.58 (0.88)
Diet
Unhealthy	42,647 (56.12)	57,836 (56.48)	65,553 (56.10)	39,629 (56.25)	27,922 (55.83)	22,108 (56.24)	60,784 (56.32)	94,851 (56.31)
Healthy	33,339 (43.88)	44,568 (43.52)	51,291 (43.9)	30,819 (43.75)	22,087 (44.17)	17,203 (43.76)	47,147 (43.68)	73,580 (43.69)
Hypertension
No	51,855 (68.24)	69,997 (68.35)	80,305 (68.73)	48,215 (68.44)	34,493 (68.97)	26,790 (68.15)	73,786 (68.36)	115,303 (68.46)
Yes	24,131 (31.76)	32,407 (31.65)	36,539 (31.27)	22,233 (31.56)	15,516 (31.03)	12,521 (31.85)	34,145 (31.64)	53,128 (31.54)
Ethnicity
White	70,149 (92.32)	97,785 (95.49)	114,020 (97.58)	69,447 (98.58)	48,522 (97.03)	37,127 (94.44)	101,700 (94.23)	164,052 (97.40)
Asian or Asian British	377 (0.50)	438 (0.43)	406 (0.35)	215 (0.31)	232 (0.46)	203 (0.52)	447 (0.41)	554 (0.33)
Black or Black British	2,694 (3.55)	1,791 (1.75)	841 (0.72)	245 (0.35)	330 (0.66)	741 (1.88)	2,864 (2.65)	1,636 (0.97)
Other ethnic group	1,665 (2.19)	1,277 (1.25)	761 (0.65)	237 (0.34)	542 (1.08)	699 (1.78)	1,632 (1.51)	1,067 (0.63)
BMI (kg/m2)
<25	23,545 (30.99)	35,274 (34.45)	37,321 (31.94)	18,510 (26.27)	13,824 (27.64)	12,377 (31.48)	35,644 (33.02)	52,805 (31.35)
25 to <30	31,997 (42.11)	43,818 (42.79)	51,863 (44.39)	31,418 (44.60)	20,508 (41.01)	16,970 (43.17)	47,117 (43.65)	74,501 (44.23)
30 to <35	14,415 (18.97)	16,882 (16.49)	20,492 (17.54)	14,671 (20.83)	10,576 (21.15)	7,145 (18.18)	18,524 (17.16)	30,215 (17.94)
≥35	6,029 (7.93)	6,430 (6.28)	7,168 (6.13)	5,849 (8.30)	5,101 (10.20)	2,819 (7.17)	6,646 (6.16)	10,910 (6.48)
Smoking status
Never	42,038 (55.32)	57,098 (55.76)	61,791 (52.88)	31,171 (44.25)	24,644 (49.28)	20,406 (51.91)	58,572 (54.27)	88,476 (52.53)
Former	27,086 (35.65)	38,425 (37.52)	45,564 (39)	28,176 (40.00)	19,185 (38.36)	15,109 (38.43)	41,426 (38.38)	63,531 (37.72)
Current	6,862 (9.03)	6,881 (6.72)	9,489 (8.12)	11,101 (15.76)	6,180 (12.36)	3,796 (9.66)	7,933 (7.35)	16,424 (9.75)
Alcohol status
Never	6,565 (8.64)	3,947 (3.85)	3,312 (2.83)	2,226 (3.16)	2,787 (5.57)	1,535 (3.9)	4,531 (4.20)	7,197 (4.27)
Former	4,731 (6.23)	2,957 (2.89)	3,053 (2.61)	2,898 (4.11)	2,682 (5.36)	1,204 (3.06)	2,995 (2.77)	6,758 (4.01)
Current	64,690 (85.13)	95,500 (93.26)	110,479 (94.55)	65,324 (92.73)	44,540 (89.06)	36,572 (93.03)	100,405 (93.03)	154,476 (91.71)
Physical activity
Low	15,066 (19.83)	18,129 (17.70)	20,682 (17.70)	14,166 (20.11)	10,321 (20.64)	7,720 (19.64)	19,474 (18.04)	30,528 (18.12)
Moderate	36,352 (47.84)	52,140 (50.92)	60,312 (51.62)	34,609 (49.13)	24,349 (48.69)	20,324 (51.7)	55,925 (51.82)	82,815 (49.17)
High	24,568 (32.33)	32,135 (31.38)	35,850 (30.68)	21,673 (30.76)	15,339 (30.67)	11,267 (28.66)	32,532 (30.14)	55,088 (32.71)
Qualification
College or University	18,156 (23.89)	31,838 (31.09)	39,816 (34.08)	21,166 (30.04)	14,119 (28.23)	14,996 (38.15)	35,453 (32.85)	46,408 (27.55)
A levels/AS levels	7,032 (9.25)	10,969 (10.71)	12,755 (10.92)	7,201 (10.22)	5,358 (10.71)	4,660 (11.85)	11,525 (10.68)	16,414 (9.75)
O levels/GCSEs	15,379 (20.24)	21,616 (21.11)	24,201 (20.71)	14,444 (20.50)	10,778 (21.55)	7,909 (20.12)	22,547 (20.89)	34,406 (20.43)
CSEs or equivalent	3,530 (4.65)	3,671 (3.58)	4,025 (3.44)	2,807 (3.98)	2,033 (4.07)	1,211 (3.08)	3,965 (3.67)	6,824 (4.05)
NVQ or HND or HNC	5,987 (7.88)	7,096 (6.93)	7,638 (6.54)	5,502 (7.81)	3,636 (7.27)	2,329 (5.92)	7,147 (6.62)	13,111 (7.78)
None of the above	21,259 (27.98)	20,891 (20.40)	21,167 (18.12)	14,995 (21.29)	10,974 (21.94)	5,980 (15.21)	20,809 (19.28)	40,549 (24.07)
Income
Less than £18,000	25,578 (33.66)	28,916 (28.24)	28,975 (24.80)	19,008 (26.98)	14,582 (29.16)	9,285 (23.62)	27,803 (25.76)	50,807 (30.16)
18,000 to 30,999	21,365 (28.12)	29,647 (28.95)	33,384 (28.57)	19,568 (27.78)	14,204 (28.40)	10,581 (26.92)	30,692 (28.44)	48,487 (28.79)
31,000 to 51,999	16,641 (21.90)	24,072 (23.51)	29,232 (25.02)	17,027 (24.17)	11,713 (23.42)	9,919 (25.23)	26,401 (24.46)	38,939 (23.12)
52,000 to 100,000	10,295 (13.55)	15,875 (15.50)	19,866 (17.00)	11,871 (16.85)	7,684 (15.37)	7,299 (18.57)	18,249 (16.91)	24,675 (14.65)
Greater than 100,000	2,107 (2.77)	3,894 (3.80)	5,387 (4.61)	2,974 (4.22)	1,826 (3.65)	2,227 (5.67)	4,786 (4.43)	5,523 (3.28)

A, Advanced; AS, Advanced Subsidiary; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CSE, Certificate of Secondary Education; GCSE, General Certificate of Secondary Education; HDL, high-density lipoprotein; HNC, Higher National Certificate; HND, Higher National Diploma; LDL, low-density lipoprotein; NVQ, National Vocational Qualification; O, Ordinary; SD, standard deviation; UK Biobank, United Kingdom Biobank.