J. Yan, K. Zheng, X. Zhang, Y. Jiang
Department of Nephrology, Chongqing General Hospital, Chongqing, 401147, China
Corresponding Author: Yingsong Jiang, MD, PhD, Department of Nephrology, Chongqing General Hospital. No.118 Xingguang Avenue, Liangjiang New Area, Chongqing, 401147, China. Phone: +86-023-63532631, Fax: +86-023-63508599.
J Prev Alz Dis 2023;
Published online January 12, 2023, http://dx.doi.org/10.14283/jpad.2023.7
Background: This study aimed to investigate the association between fructose consumption and all-cause dementia, and Alzheimer’s disease (AD) dementia.
Methods: We used data from the Framingham Offspring Study (FOS) Cohort exams 5 through 9. Fructose consumption was quantified using a food-frequency questionnaire (FFQ) at cohort examinations 5 and participants were dementia-free at baseline. Surveillance for incident events commenced at examination 9 through 2014. Multivariable Cox proportional hazards regression was used to estimate the hazard ratios for the association between fructose consumption and incidence of all-cause dementia and AD dementia.
Results: Over a mean follow-up of 15.2 (interquartile range, 12.3-17.1) years (31715.1 person-years), there were 233 dementia events of which 163 were AD dementia (70.0%). After multivariate adjustments, individuals with the highest consumption of fructose had a higher risk of all-cause dementia, and AD dementia when comparing daily cumulative consumption to 0 per week (reference), with HRs of 1.49 (95% 1.14-1.84, P for trend < 0.001) for all-cause dementia, and 1.60 (95%CI 1.22-2.01, P-trend < 0.001) for AD dementia. And the comparable results were shown in the subgroups for individuals with median consumption of fructose.
Conclusion: Fructose consumption was associated with a higher risk of all-cause dementia and AD dementia.
Key words: Fructose, dementia, Alzheimer’s disease, Framingham Offspring Study, risk factors.
The population is aging worldwide, leading to an increasing global burden of dementia, a group of symptoms in which there is progressive deterioration in cognitive function severe enough to interfere with a person’s daily living activities, are regarded as among the most significant public health challenges largely affecting adults aged >65 y (1, 2). Dementia comprises Alzheimer’s disease (AD), which contributes to 50–70% of dementia cases, vascular dementia (VD), which contributes to ~25%, and other forms of dementia (3). However effective drug treatments to prevent significantly attenuate, or ameliorate dementia are lacking. Lifestyle-related and dietary factors associated with dementia are potentially modifiable and thus represent targets for primary prevention (4-6).
Fructose consumption, such as non-diet soda, fruit drinks, apple juice and any combination of these beverages, is excessive worldwide nowadays and has gained increasing interest in relation to health since high consumption of fructose was found to be consistently associated with an increased risk of mortality, asthma, obesity, hypertension, diabetes, and cardiovascular disease (7-9). The deleterious effects of fructose on lipid metabolism, and developing AD of excessive intake of carbohydrates, in particular, high-fructose corn syrup and artificial sweeteners, are addressed in Mediterranean diet-based cohort studies and may be resulted from the critical role of the ω-3 fatty acid docosahexaenoic acid (10-12). What’s more, the literature from animal studies suggests that increased fructose intake is associated with an increased risk of neurodegeneration and dementia (13, 14). However, to our knowledge, there is little persuasive evidence in humans at typical intake levels to examine the associations between fructose consumption and the risk of incident all-cause dementia and AD dementia. And these previous studies were limited due to the less accurate assessment for fructose and less comprehensive and solid outcomes like dementia and AD.
Hence, we examined the hypothesis that high consumption of fructose which was evaluated once at the baseline could increase the incidence of all-cause dementia and AD dementia in the community-based Framingham Offspring Study which collected detailed socio-demographic characteristics, medical history, lifestyle factors, and routine review cycles.
The Framingham Heart Study (FHS) involves a series of ongoing, prospective, population-based cohorts from the town of Framingham, MA, the USA which was established in 1948 with the aim to explore cardiovascular disease risk factors (15). We studied the Framingham Offspring Study (FOS) cohort, which commenced in 1971 with the enrollment of 5124 adults who were the children of the original cohort and their partners (16). Participants have been studied across 9 examination cycles including a series of questionnaires and laboratory tests approximately every 4 years, with the latest cycle concluding in 2014. The characteristics and study protocol have been published elsewhere (17). This study complied with the Declaration of Helsinki and all participants provided written informed consent. The study protocol was approved by the institutional review board of Chongqing General Hospital and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).
For the present study, we assessed self-reported dietary intake from participants of the FOS using a food frequency questionnaire (FFQ) administered at examination cycles 5 (1991–1995) and defined it as the baseline. Participants were excluded if they had an abnormal estimated total energy intake (<600 – >3999 kcal for females or >4199kcal for males) and/or >13 missing items. And participants with preexisting dementia and those missing follow-up were excluded as well.
Participants completed the Harvard semi-quantitative food-frequency questionnaire (FFQ) at examination cycles 5 (18). The FFQ provides a validated measure of dietary intake over the past 12 months which is comprised of a list of 126 foods with a standard serving size and a selection of 9 frequency categories ranging from never or<1 per month to>6 per day. The FFQ also allowed participants to include ≤4 extra food items that were essential elements of their diets but were not included among the items on the FFQ. In addition, the FFQ included questions on mostly used breakfast cereal, types of fats and oils, and frequency of consumption of fried foods. Intakes of food components (i.e., nutrients, food items, or food groups) were computed by multiplying the frequency of consumption of each food item by the nutrient content of the specified portions (18).
We combined FFQ items including non-diet soda, fruit drinks, apple juice, and any combination of these beverages to create variables reflecting intake of fructose. The suggested serving size for fruit and soft drinks was a can or glass, as compared with a small glass for juice. Cut points were determined before conducting the main analyses based on the relative distribution of intake for each variable. Total fructose consumption was examined as <1 serving per day (reference), 1 – 7 servings per day, and >7 servings per day. Details were further described in FHS coding manual (http://www.framinghamheartstudy.org/share/coding_manuals/).
Ascertainment of dementia and AD
All FHS participants were under ongoing continuous surveillance for onset of cognitive impairment and clinical dementia which commenced from examination cycle 5 to the time of incident event or until last known contact with the participant. The full methods for dementia surveillance and flagging of suspected cognitive impairment are described in the eMethods in the Supplement. A diagnosis of dementia was made in line with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Participants with AD met the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for definite (autopsy cases only), probable, or possible AD (19, 20).
A number of potential confounders were considered in our analyses based on established or suspected risk factors for dementia. And the most recent covariate information was exam 5. We calculated nutrient, energy intake, alcohol consumption, sugar in beverage, sea foods, leafy vegetables, blueberries, red meat, fried food, cheese, and animal fat intake 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. Physical activity [measured by the physical activity index (PAI), a composite score calculated by summing up the products of hours at each level of activity times] (21). The educational levels, personal income, marital status were assessed by medical interview. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL), uric acid, and glucose were measured after an overnight (>10 hours) fast.
Descriptive statistics were performed for the 3 subgroups: participants with no intake of fructose, 1-7 servings/week, and >7 servings/week. Mean and standard deviation (SD) were calculated for continuous variables and absolute and relative frequencies for discrete data. And they were analyzed by the student t-test and chi-square test respectively among different subgroups. Follow-up for all-cause dementia and AD dementia was from the baseline examination to the time of the incident event or the date the participant was last known to be dementia-free. The associations between fructose intake and incident outcomes were fitted in Cox proportional hazards regressions with the duration of follow-up in years as the timescale and the lowest category of fructose intakes as the reference. Hazard ratios (HR) are presented accompanied by 95% confidence intervals (CIs).
Three models were applied in our analyses: crude analysis; Model 1 was adjusted for sex, age, MMSE at baseline, and education level; Model 2 was additionally adjusted for SBP, treatment of hypertension, LDL, uric acid, prevalent diabetes mellitus, current smoking, alcohol consumption, dietary fiber intake, total energy intake, sugar in beverage, seafood, red meat, fried foods, animal fat, personal income, marital status, physical activity index, and BMI. Kaplan-Meier curves were used with adjustment for confounding to describe all-cause dementia and AD dementia risk according to fructose consumption. Analyses were performed using Stata statistical software, version 15 (Stata Corporation, College Station, Texas, USA). A 2-sided with P<0.05 was considered statistically significant. All analyses were performed based on a predefined statistical analysis plan (available on request).
Of the 3702 participants of the FHS Offspring Cohort attending the 5th exam, 2950 subjects completed the FFQ examination, and 391 were excluded due to the implausible food intake information. Furthermore, 405 subjects were excluded because 341 lacked information for dementia, 24 subjects were diagnosed with dementia at baseline and 40 were lost during the follow-up. Thus, 2154 individuals could be included in the final analyses (See Figure 1).
Descriptive data are presented in Table 1. Compared with participants with the lowest fructose intake, participants with higher intake were more likely to be male, young, to have a higher intake of total calories, saturated fat, dietary fiber, sugar in beverage, sea foods, red meat, fried foods and animal fat, and to get a higher physical activity index, uric acid, income, and education levels.
Continuous variables were expressed as mean ± SD and categorical variables as number and percentage. Abbreviations: BMI, body mass index; WC, waist circumference; LDL, low-density lipoprotein; TC, total cholesterol; MMSE, mini-mental state examination.
Fructose and risk for all-cause dementia and AD dementia
During a mean follow-up of 15.2 (interquartile range, 12.3-17.1) years (31715.1 person-years), a total of 233 incident dementia events occurred, including 163 (70.0%) cases of AD dementia.
After adjustment for sex, age, MMSE at baseline, education level, SBP, treatment of hypertension, LDL, uric acid, prevalent diabetes mellitus, current smoking, alcohol consumption, dietary fiber intake, total energy intake, sugar in beverage, seafood, red meat, fried foods, animal fat, personal income, marital status, physical activity index, and BMI in the Cox regression model, participants with consumption of fructose more than 7 servings/week showed a higher risk of all-cause dementia and AD dementia (HR: 1.49, 95% CI: 1.14-1.84, P for trend < 0.001 for all-cause dementia; HR: 1.60, 95% CI: 1.22-2.01, P-trend < 0.001 for AD dementia) than subjects with no consumption for fructose. And the results remained comparable for participants with medium consumption of fructose (HR: 1.46, 95% CI: 1.30-1.79, for all-cause dementia; HR: 1.52, 95% CI: 1.14-1.91, for AD dementia) (see Table 2). Figure 2 shows the cumulative incidence curves for all-cause dementia and AD dementia stratified by groups with different levels of fructose consumption after adjusting for age and sex.
Model 1: Adjusted for sex, age, MMSE at baseline, and education level; Model 2: Adjusted for model 1 plus, SBP, treatment of hypertension, LDL, prevalent diabetes mellitus, current smoking, alcohol consumption, dietary fiber intake, total energy intake, sugar in beverage, seafood, red meat, fried foods, animal fat, personal income, marital status, physical activity index, and BMI; Abbreviations: AD, Alzheimer’s disease; MMSE, mini-mental state examination; SBP, systolic blood pressure; LDL, low-density lipoprotein; BMI, body mass index.
Data are for cumulative incidence of (A) all dementia, and (B) AD dementia among participants based on fructose intake in the Framingham Offspring Study. Adjustments were made for age and sex; Abbreviations: AD, Alzheimer disease.
In this population-based, longitudinal FOS cohort, our results showed that higher consumption of fructose was associated with an increased risk of incident all-cause dementia and AD dementia. These findings were robust given that they were observed even after statistical adjustment for numerous confounders and provide compelling evidence that limiting the consumption of fructose could be beneficial for the cognition health of people.
The use of fructose, which is an isomer of glucose and a natural sugar found in many fruits, as a sweetener has exponentially increased, either as simple sugar (sucrose) or in the form of high-fructose corn syrup(HFCS), and fructose intake now accounts for ~15% of the daily caloric intake of US adolescents (22, 23). Approximately 80% of added sugars in soft drinks, baking products, and ice creams consist of HFCS (24). To be exact, the rise in fructose consumption over the past two decades is a major change in US dietary intake, which has paralleled the unabated obesity epidemic in youth and increased risks of mortality, cardiovascular disease, asthma, and metabolic diseases (25). Results from animal studies suggest that fructose intake may be associated with cognitive decline. Stranahan et al. found that a high-calorie diet with HFCS reduces hippocampal synaptic plasticity and impairs cognitive function, possibly via the development of insulin resistance (14). Ross et al. reported that the high fructose diet did not affect acquisition of the task, but did impair performance on the retention test and spatial (hippocampal-dependent) memory in male rat. And the retention deficits correlated significantly with fructose-induced elevations of plasma triglyceride concentrations (13). Agrawal et al reported that high-dietary fructose consumption leads to an increase in insulin resistance index, and insulin and triglyceride levels, which characterize metabolic syndrome. Rats fed on an omega-3 FAs deficient diet showed memory deficits in a Barnes maze, which were further exacerbated by fructose intake (26). From the human studies aspects. A cross-sectional study including 737 participants without diabetes, aged 45–75 years, from the Boston Puerto Rican Health Study, showed that added sugars (sucrose and HFCS) were significantly associated with lower MMSE scores, after adjusting for covariates and Adjusted OR for cognitive impairment (MMSE < 24) was 2.28 (95% CI 1.26-4.14) for added sugars, comparing the highest with lowest intake quintiles (27). A longitudinal study recruiting 2888individuals revealed that artificially sweetened soft drink which was rich in HFCS was associated with a higher risk of stroke and dementia, but sugar-sweetened beverages were not (28). Stephan et al speculated that increasing intake of fructose could lead to greater dementia risk either directly only or more likely in synergic combination with the concomitant increases in obesity, but lacking evidence in epidemical studies (29). And a prospective study over an average follow-up of 19 years based on FOS demonstrated that sugar in beverage consumption was associated with an increased risk of all dementia, AD dementia and stroke independent from multiple demographic factors (30). To our knowledge, our study is the first to report an association between daily intake of fructose and an increased risk of both all-cause dementia and AD dementia based on a well-organized population-level cohort, an accurate assessment for diet, and a standard diagnosis and subtype flow of dementia.
Several hypotheses could explain our findings. Firstly, fructose is readily absorbed and rapidly metabolized by the liver and could lead to a rapid spike in blood glucose and insulin and a stimulation of lipogenesis and TG accumulation as well, which in turn contributes to reduced insulin sensitivity and hepatic insulin resistance/glucose intolerance as called metabolic syndrome, providing a plausible mechanism to link consumption to the development of dementia risk factors (31-35). Secondly, fructose might delay the trigger of the internal satiety signal, leading to excessive caloric ingestion, and further contributing to weight gain and the risk of overweight or obesity, the latter being recognized as a major risk factor for dementia, although the relatively small number of subjects in our study could lead to the lack of statistical significance for greater intakes could be more likely obesity (36). Thirdly, excessive fructose intake has also been linked to high uric acid. Elevated UA levels represent a biomarker of increased activity of the xanthine oxidase, which, via an increased generation of reactive oxygen species and reduced levels of NAPDH, could reduce the NO synthesis, which causes insufficient NO production and aggravates oxidative stress before inducing cerebrovascular endothelial dysfunction, while neuronal NOS is overactive and can produce excessive NO to cause neurotoxicity. Finally, the risk of dementia was increased consequently (29, 37). What’s more, high fructose intake can directly or indirectly induce protein degeneration by increasing the formation of glycated proteins and oxidative stress, both of which could be the pathophysiological mechanism for dementia (38). Finally, people with a high intake of fructose may take an unhealthy lifestyle as well. The Nurses Health Study and Health Professionals Follow-Up Study reported that participants with greater consumption of sugar and artificially sweetened soft drinks were more likely to smoke regularly and take a sedentary lifestyle both of which were confirmed as the risk factors for dementia (39).
Strengths of this study include our large population-based sample, the ability to comprehensively investigate cognition by using a wide range of cognitive tests and standard surveillance, diagnosis, and subtype for dementia, and the comprehensive and accurate assessment for a daily diet based on the FFQ. What’s more, we were able to adjust for many important confounders, including lifestyle and risk factors for dementia. However, some limitations need to be taken into account. First, we used an FFQ to assess dietary intake, which is subject to measurement error and recall bias. And to account for potential systematic measurement error, we adjusted our analyses for total energy intake. Second, we are unable to infer causality since the observational nature of our study, and due to the relatively small number of participants and events, it is impossible to clarify the dose-effect relationship between fructose intake and dementia. Third, our analyses were also limited in that we could not account for certain dementia risk factors that were not available to us in the public dataset, such as genotype liking APOE ε4. Therefore, residual confounding may have affected our estimates, despite several potentially important confounding factors being taken into account. Fourth, we did not adjust for multiple comparisons meaning that some findings may be attributable to chance. Fifth, diet is complex and includes interactions between different food groups and nutrients, but we only explored a single food group even some diet risk factors for dementia were adjusted. Sixth, it was a retrospective cohort study whose original cohort was mainly focused on cardiovascular disease, hence detailed information for special types such as Lewy body dementia, and conditions that may affect the risk for dementia, such as normal pressure hydrocephalus and neurofibrillary tangles were lacked. Finally, participants included in our study were mainly white and of European descent, limiting the generalizability of our findings to populations of non-European descent.
In conclusion, our findings are an important addition to the limited evidence that higher fructose consumption could increase the risk of all-cause dementia and AD dementia, independent of multiple dementia factors. These findings also add to the evidence that diet could be an important contributor to all-cause dementia and AD dementia risk and more specific public health guidance could be indicated to limit the intake of fructose. However further researches in larger and more racially and ethnically diverse subjects are warranted to confirm our findings and to investigate the underlying mechanisms.
Acknowledgments: We thank the National Heart, Lung, and Blood Institute (NHLBI), Framingham Heart Study (FHS) and the Chongqing General Hospital.
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.
Grant Support: None.
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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