H. Miao1,*, K. Chen2,*, X. Yan3, F. Chen4
1. Department of Endocrinology, Jiangjin Central Hospital of Chongqing, Chongqing, China; 2. Out-Patient Department, Jinzi Mountain Hospital of Chongqing Mental Health Center, Chongqing, 401147, China; 3. Department of Pediatrics, Jiangjin Central Hospital of Chongqing, Chongqing, China; 4. Department of Geriatrics, Chongqing Mental Health Center, Chongqing, China; * Hongyun Miao and Ken Chen are co-first author
Corresponding Author: Fei Chen, First Psychogeriatric Ward, Jinzi Mountain Hospital of Chongqing Mental Health Center, No102, Jinzi Mountain, Jiangbei, District, Chongqing, 401147, China. Phone:+86-023-67511695, Fax: +86-023-67511695, e-mail: email@example.com; Xiaoyong Yan, Department of Pediatrics, Jiangjin Central Hospital of Chongqing , No.725 Jiangzhou Street, Jiangjin District, Chongqing,402260,China. Phone: +86-023-475213
J Prev Alz Dis 2020;
Published online November 9, 2020, http://dx.doi.org/10.14283/jpad.2020.62
Background: This study aimed to investigate the association between sugar in beverage and dementia, Alzheimer Disease (AD) dementia and stroke.
Methods: This prospective cohort study were based on the US community-based Framingham Heart Study (FHS). Sugar in beverage was assessed between 1991 and 1995 (5th exam). Surveillance for incident events including dementia and stroke commenced at examination 9 through 2014 and continued for 15-20 years.
Results: At baseline, a total of 1865 (63%) subjects consumed no sugar in beverage, whereas 525 (18%) subjects consumed it in 1-7 servings/week and 593 (29%) in over 7 servings/week. Over an average follow-up of 19 years in 1384 participants, there were 275 dementia events of which 73 were AD dementia. And 103 of 1831 participants occurred stroke during the follow-up nearly 16 years. After multivariate adjustments, individuals with the highest intakes of sugar in beverage had a higher risk of all dementia, AD dementia and stroke relative to individuals with no intakes, with HRs of 2.80(95%CI 2.24-3.50) for all dementia, 2.55(95%CI 1.55-4.18) for AD dementia, and 2.11(95%CI 1.48-3.00) for stroke. And the same results were shown in the subgroup for individuals with median intakes of sugar in beverage.
Conclusion: Higher consumption of sugar in beverage was associated with an increased risk of all dementia, AD dementia and stroke.
Key words: Sugar in beverage, dementia, Alzheimer disease, stroke, Framingham Heart Study.
Dementia is a major cause of disability among the elderly and its medical and economic burdens on society have been increasing worldwide (1). Recent population-based studies have reported that lifestyle-related diseases such as hypertension (2), diabetes as well as lifestyle factors such as smoking habits (3, 4), alcohol consumption and dietary patterns are associated with the risk of incidence of dementia and AD (5, 6). However, the influence of particular individual dietary components at habitual intake amounts on dementia, especially Alzheimer disease (AD) dementia and stroke which share common risk factors and etiologies with dementia, remains incompletely understood (5).
Sugar consumption is excessive worldwide nowadays, which is widely recognized as key dietary risk factors for obesity and poor cardiometabolic health (7, 8). And longitudinal studies indicate that frequent sugar-sweetened beverages consumption is associated with a higher risk of type 2 diabetes and cardiovascular disease and raises the possibility that higher concentrations of ceramide which is associated with adverse metabolic health (9). Moreover, to our knowledge, studies yet showed that higher intake of sugary beverages was associated cross-sectionally with markers of preclinical AD and the risk of incident dementia (10, 11). Generalizability of these findings was limited due to the less accurate for sugar in beverage and less comprehensive outcomes only including dementia or preclinical AD without stroke.
Accordingly, the primary aim of this study was to examine whether sugar in beverage were associated with the 15-year risks of incident dementia and stroke in the community-based Framingham Heart Study (FHS) with detailed review of all medical records and autopsies. And we aimed to further investigate the underlying mechanisms by taking into account socio-demographic characteristics, medical history, and lifestyle factors.
This study was carried out as a secondary analysis of data from the population-based FHS. The FHS is a longitudinal multi-generational study conducted in Framingham, MA, USA (12). The original cohort started in 1949 and consisted initially of 5209 respondents of a random sample of two-thirds of the adult population characterized by absence of atherosclerotic cardiovascular disease. The ‘Framingham Offspring Study’ was initiated in 1971 as a sample (n=5 5124, age = 12–58 years) consisting of the surviving descendants of the original cohort participants and spouses of those descendants. Since their recruitment, participants from the Offspring cohort have had 9 serial examinations including standardized interviews, physician examinations, and laboratory testing. The characteristics and study protocol of both cohorts have been published elsewhere. For the present investigation, we included participants of the offspring cohort who were examined between 1990 and 1994 and for whom data of a detailed pain examination were available. This study complied with the Declaration of Helsinki; written informed consent was obtained from all study participants. The National Heart, Lung, and Blood Institute (NHLBI) of National Institutes of Health (NIH) has approved the study protocol.
Sugar in beverage assessment
Over the study course, Participants completed the Harvard semi quantitative FFQ at examination 5. For further details, see https://biolincc.nhlbi.nih.gov/studies/framoffspring. This FFQ is designed to measure dietary intake over the past year and has been validated extensively. Participants were asked how often they consumed one glass, bottle, or can of each sugary beverage item, on average, across the previous year. Each item was scored according to nine responses spanning from “never or almost never” to “61 per day.” Participants were presented with three items on sugar-sweetened soft drink (“Coke, Pepsi, or other cola with sugar,” “caffeine-free Coke, Pepsi, or other cola with sugar, “and “other carbonated beverages with sugar”), four items on fruit juice (“apple juice,” “orange juice,” “grapefruit juice,” and “other juice”), one item on sugar-sweetened fruit drinks and three items on diet soft drink (“low-calorie cola with caffeine,” “low-calorie caffeine-free cola,” and “other low-calorie beverages”). The individual items were summed to create exposure variables reflecting intake of (I) total sugary beverages (excluding diet soft drinks), (II) fruit juice, (III) sugar-sweetened soft drinks (all sugary beverages excluding diet soft drink, fruit juice, and fruit drinks), and (IV) diet soft drinks. Total sugary in beverage consumption was examined as 0-140 servings per week and was further categorized into a three-level variable: none intake (0 serving/week), 1-7 servings/week and >7 servings/week. Moreover, intake of sugary in beverages ascertained via the FFQ is reliable when measurements are repeated after 12 months, with correlation coefficients ranging from 0.85 for cola and 0.86 for fruit juice. Details were further described in FHS coding manual (http: //www.framinghamheartstudy.org/share/coding_ manuals/vr_ffreq_ex05_1_0575d_coding_manual.pdf).
Ascertainment of dementia and AD
All FHS participants were under ongoing continuous surveillance for onset of cognitive impairment and clinical dementia. We related beverage consumption to the 15-year risk of dementia. Surveillance commenced from examination cycle 5 to the time of incident event over a maximum of 41 years or until last known contact with the participant. A diagnosis of dementia was made in line with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. A diagnosis of Alzheimer’s disease (AD) dementia was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association for definite, probable, or possible AD. See the online-only data supplement for complete details on our methods of surveillance, diagnosis, and case ascertainment on dementia and AD (14, 15). (eMethods in the Supplement).
Ascertainment of stroke
Stroke incidence was assessed through the continuous monitoring of hospital admissions in Framingham and by reviewing all available medical records and results (16). Stroke was defined as focal neurological symptoms of rapid onset and presumed vascular origin, lasting >24 hours or resulting in death within 24 hours. A committee comprising of least 3 FHS investigators, including at least 2 neurologists, adjudicated stroke diagnosis. The committee considered all available medical records, brain imaging, cerebrovascular imaging, and the assessment of the study neurologist who visited the participant. See more details on the FHS code manual (http: //www.framinghamheartstudy.org/share/coding_manuals/vr_survstk_2014_a_1031s_coding_manual_v1.pdf).
The most recent covariate information during the period of sugar in beverage assessment (Exam 5). We calculated nutrient, energy intake and alcohol consumption from the aforementioned FFQ. Hypertension was defined as systolic blood pressure>140 mm Hg, diastolic blood pressure>90 mm Hg, or use of antihypertensive medications. Individuals with fasting plasma glucose concentrations≥7 mmol/L or who self-reported use of antidiabetic medications were considered diabetic. BMI was calculated as kg/m2. Waist circumference (in inches) was measured at the level of the umbilicus. Current smokers were defined as participants who smoked regularly in the year preceding examination cycle 5.The educational level were assessed by medical interview. Total cholesterol, low-density lipoprotein cholesterol and glucose were measured after an overnight (>10 hours) fast.
Descriptive statistics was performed for the 3 subgroups: participants with no intake for sugar in beverage, 1-7 servings/week and >7 servings/week. For continuous variables mean, standard deviation and range were calculated for approximately normally distributed data, otherwise median and range were used. For discrete data, absolute and relative frequencies were computed. Follow-up for dementia and stroke was from the baseline examination to the time of incident event. And for persons with no incident events, follow-up was censored at the time of death or the date the participant was last known to be dementia free. For survival analysis, Cox proportional hazards modelling was applied and the following covariates were included: crude analysis; Model 1 adjusted for age and sex; Model 2 adjusted for age, sex, and the following dementia risk factors: hypertension, smoking, diabetes and body mass index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The same analysis was carried out for Alzheimer’s disease and stroke. Analyses were performed using SAS software, version 9.4 (SAS Institute Inc, Cary, North Carolina) and Stata statistical software, version 15 (Stata Corporation, College Station, Texas, USA). A 2-sided with P<0.05 was considered statistically significant.
Of the 3702 participants of the FHS Offspring Cohort attending the 5th exam, 2983 subjects underwent the sugar in beverage examination and thus were included in this study. Thereof, 770 subjects were excluded because 730 subjects lacked assessment on dementia, 4 subjects were diagnosed with dementia at baseline and 36 subjects were lost follow-up. Thus, 2664 subjects could be included in the final analyses for dementia, with 1865(63%) subjects with no intake for sugar in beverage, 525(18%) subjects with 1-7 servings/week and 593(29%) subjects with over 7 servings/week. And 2916 subjects were available for incident stroke analysis, since 40 lacked assessment on dementia and 13 were lost follow-up. See Figure 1.
Descriptive data are presented in Table 1. The initial health status was comparable between both groups. The three groups descriptively differed with regard to age, sex, BMI, total caloric intake, saturated fat, dietary fiber, smoking status and history of diabetes. See Table 1.
Abbreviations: BMI, body mass index; WC, waist circumference. LDL, low-density lipoprotein, TC: total cholesterol.
Sugar in beverage and Risk for Dementia and stroke
The mean follow-up time for dementia was 19 years (interquartile range, 18-20years) and for stroke was 16 years (interquartile range, 15-18 years).The absolute number of all dementia events over the follow-up was 553 including 142 for AD dementia. And 203 stroke occurred during the follow-up.
When adjusting for age, sex, diabetes, hypertension, smoking and BMI using Cox regression analysis, subjects with more than 7 servings/week of sugar in beverage showed a higher risk of all dementia, AD dementia and stroke [HR 2.80 (2.24-3.50) for all dementia; 2.55(1.55-4.18) for AD dementia; 2.11(1.48-3.00) for stroke] than subjects with no intake for sugar in beverage. And the results were comparable for participants with 1-7 servings/week of sugar in beverage [HR 2.65(2.14-3.30) for all dementia; 2.49(1.55-3.99) for AD dementia; 1.94(1.38-2.72) for stroke] (Table 2.).And the results were comparable when limiting the age to over 65 years for incidence of dementia and AD dementia, but not for the stroke which may be resulted from the rare stroke events occurred (eTable 1 in supplement). Figure 2 shows the cumulative incidence curves for all dementia, AD dementia and stroke stratified by groups with different levels of sugar in beverage intake after adjusting for age and sex.
Abbreviations: AD, Alzheimer’s disease; HR, hazard ratio; CI, confidence interval; Model 1 Sex and Age; Model 2 in addition for hypertension, smoking, diabetes and body mass index.
In our longitudinal analysis of a large community-based sample, it is found that higher consumption of sugar in beverage was associated with an increased risk of all dementia, AD dementia and stroke at the same time. These findings were striking given that they were evident in a middle-aged sample and were observed even after statistical adjustment for numerous confounders such as sex, age, hypertension, diabetes and BMI.
Excess intake of sugar in beverage is known to be associated with cardiovascular disease and metabolic disease, which, in turn, is associated with vascular brain injury (17, 18). Although this suggests a possible link between sugary beverage consumption and vascular brain injury, we observed more striking associations between sugar in beverage and incidence of dementia and AD dementia. The Nurses’ Health Study and Health Professionals Follow-Up Study reported that higher consumption of sugar and artificially sweetened soft drinks was each independently associated with a higher risk of incident stroke over 28 years of follow-up for women and 22 years of follow-up for men (19). On the contrast, a prospective cohort study including 2888 participants reported an association between daily intake of artificially sweetened soft drink and an increased risk of both all-cause dementia and dementia because of AD, but not sugar-sweetened (10). Stephan and colleagues speculated that high fructose intake is a risk factor for dementia and that increasing consumption of fructose in the U.S. population could lead to greater dementia risk, but there is little persuasive evidence in humans at typical intake levels (20). In a cross-sectional observations in a large community-based sample, higher sugary beverage intake was associated with markers of preclinical AD, including brain atrophy and poorer episodic memory (11). To our knowledge, our study is the first to demonstrate accelerated probability of developing all dementia, AD dementia and stroke year-on-year at a population level and much more accurate assessments for sugar in beverage. And it is not a cross-sectional observations, but a long-term implications, especially for more than 5-year follow-up. In detail, it is like a fraud that excessive consumption of sugar in beverage is safe in the short term like less than 5-year follow-up, but would increase the risk of dementia, AD dementia and stroke in the long term. And only in a prospective study the truth can be told.
First, the metabolic changes followed by intake of sugar in beverage may harm cognitive function and lead to stroke, although the mechanisms are incompletely understood, and inconsistent findings have been reported. Sugar in beverage leading to a rapid rise in blood glucose and insulin, providing a plausible mechanism to link the sugar in beverage consumption to the development of dementia and stroke risk factors (21). A study shown that long term consumption of sucrose-sweetened water led to increased body weight, glucose intolerance, insulin resistance, and hypercholesterolemia and were associated with exacerbation of spatial learning and memory impairment and cerebral Aβ deposition in transgenic mouse model of AD (22). Also in animal models, high fat refined sugar diets increase Aβ aggregation and plasma total tau level, hippocampal atrophy, and reduce levels of brain-derived neurotropic factor (BDNF) which could lead to impaired memory performance and reduced synaptic plasticity within the hippocampus (11, 23, 24). Secondly, the association may be mediated by lifestyle factors related to high intake of sugar in beverage. A study recruiting 640 adolescents suggested that sugar-sweetened beverage intake may attenuate the beneficial effects of physical activity on skeletal muscle mass and lead to obesity (25). A survey demonstrated that individuals who consumed diet beverages were simply more likely to smoke regularly like what is showed in our baseline characters (26). And it is confirmed that low physical activity and muscle mass, obesity and smoking regularly were risky for incident dementia (4, 27-29). In a large, dementia-free community-dwelling cohort, our results provide further evidence that sugar in beverage consumption is associated with increased risk of all dementia, AD dementia and stroke after adjustment for confounders including sex, age, BMI, diabetes and hypertension. These findings are highly relevant given that dementia and stroke are two of the largest global public health challenge interfering with a person’s daily living activities facing our aging population.
The main strength of our study was the use of a large and well-characterized community-based sample free of clinical stroke and dementia based on FHS which collected detailed dietary, lifestyle, clinical data and accurate assessment for sugar in beverage. Limitations of our study include the observational nature of the study, which precludes conclusions about causality and the temporal associations between sugar in beverage intake and dementia, AD dementia and stroke. Second, the use of a self-report FFQ to quantify sugar in beverage intake data may be subject to recall bias. Third, there is multifactor affecting the relationship between sugar in beverage and cognitive decline. Although we addressed confounding in numerous ways, we cannot exclude the possibility of residual confounding.
In conclusion, the findings of this research demonstrate that sugar in beverage consumption was associated with an increased risk of all dementia, AD dementia and stroke independent from multiple demographic factors. These finding may help to further advise people consume less sugar in beverage to keep better health. Future research is needed to replicate our findings and to investigate the mechanisms underlying the reported associations.
Data Availability: Data described in the manuscript, code book, and analytic code will not be made available because the authors are prohibited from distributing or transferring the data and codebooks on which their research was based to any other individual or entity under the terms of an approved NHLBI Framingham Heart Study Research Proposal and Data and Materials Distribution Agreement through which the authors obtained these data.
Conflicts of Interest: The authors declare that they have no conflicts of interest.
Acknowledgments: The authors thank the National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, Chongqing Mental Health Center and Jiangjin Central Hospital of Chongqing.
Grant Support: None. All authors have read the journal’s authorship agreement and that the manuscript has been reviewed by and approved by all named authors.
Ethical Standards: The study procedures followed were in accordance with the ethical standards of the Institutional Review Board and the Principles of the Declaration of Helsinki.
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