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CRITICAL VALUES OF DAILY SEDENTARY TIME AND ITS LONGITUDINAL ASSOCIATION WITH MILD COGNITIVE IMPAIRMENT CONSIDERING APOE Ε4: A PROSPECTIVE COHORT STUDY

 

H. Duan1,7,8, X. He1,7,8, T. Yang2,7,8, N. Xu1,7,8, Z. Wang1,7,8, Z. Li1,7,8, Y. Chen2,7,8, Y. Du3,7,8, M. Zhang1,7,8, J. Yan3,7,8, C. Sun4, G. Wang5, F. Ma2,7,8, W. Li1,7,8, X. Li6, G. Huang1,7,8,9

 

1. Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China; 2. Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China; 3. Department of Social Medicine and Health Management, School of Public Health, Tianjin Medical University, Tianjin, China; 4. Neurosurgical Department of Baodi Clinical College of Tianjin Medical University, Tianjin, China; 5. Department of Tumor, Baodi Clinical College of Tianjin Medical University, Tianjin, China; 6. Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, China; 7. Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, Tianjin, China; 8. Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China; 9. The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin, China.

Corresponding Author: Guowei Huang, Professor, PhD, Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No 22 Qixiangtai Road, Heping District, Tianjin 300070, China, Phone: 86-22-83336603; E-mail: huangguowei@tmu.edu.cn; Xin Li, Professor, PhD, Department of Neurology, The Second Hospital of Tianjin Medical University, No 23 Pingjiang Road, Hexi District, Tianjin 300211, China. Phone: 86-22-88328514; E-mail: lixinsci@126.com; Wen Li, Associate Professor, PhD, Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No 22 Qixiangtai Road, Heping District, Tianjin 300070, China. Phone: 86-22-83336603; E-mail: liwen@tmu.edu.cn

J Prev Alz Dis 2024;3(11):582-588
Published online February 21, 2024, http://dx.doi.org/10.14283/jpad.2024.44

 


Abstract

BACKGROUND: Long sedentary time and physical inactivity are negatively related to cognition, but the cut-off value remains unclear, and apolipoprotein E polymorphism ε4 (APOE ε4) is a known genetic risk factor of mild cognitive impairment (MCI).
OBJECTIVES: To explore longitudinal association of sedentary time and MCI, and to identify a cutoff value that increases the risk of developing MCI, taking into account APOE ε4 stratification and its interactions.
DESIGN: A prospective cohort study.
SETTING: Population-based study.
PARTICIPANTS: We included 4932 older adults from Tianjin Elderly Nutrition and Cognition (TENC) cohort study recruited from March 2018 to June 2021 with 3.11 years of median follow-up time.
MEASUREMENTS: The primary outcome was newly diagnosed MCI, which was diagnosed by a modified version of the Petersen’s criteria. The information of sedentary time (hours/day) and physical activity (MET-h/week) were obtained by questionnaire. Cox proportional hazard regression models and restricted spline curve were conducted.
RESULTS: A total of 4932 participants were included (mean [SD] age, 67.85 [4.96] years; 2627 female [53.3%] and 2305 male [46.7%]), 740 newly onset MCI patients were identified. Longer sedentary time was associated with higher risk of MCI for all participants (HR:1.069, 95%CI: 1.034, 1.105), especially in APOE ε4 non-carriers (HR:1.083, 95%CI: 1.045, 1.123) whether adjusted potential confounders. Sedentary time had synergistic interactions with APOE ε4 (β:1.503, 95%CI: 1.163, 1.942) and physical activities (β: 1.495, 95%CI: 1.210, 1.846). Restricted spline curve showed a cut-off value of 3.03 hours/day.
CONCLUSIONS: Long sedentary time (≥3.03 hours/day) could increase MCI risk, especially in APOE ε4 non-carriers, people with higher PA, aged 65 and above.

Key words: Sedentary time, APOE ε4, mild cognitive impairment, restricted spline curve, cohort study.


 

Introduction

In the context of global ageing, the cognitive health of older adults has attracted much attention. Mild cognitive impairment (MCI) is a transitional cognitive state between normal cognitive aging and dementia, in particular, Alzheimer’s disease (AD) (1). It is reported that about 10-12% MCI patients will develop AD per year (1), but this trajectory is not unidirectional, around 15.8% MCI patients will reverse to normal cognition each year (2). But there is no effective treatment for MCI at present. Therefore, it is critical to identify risk factors for MCI and implement early interventions..
Both lifestyle and genetic factors related to the development of MCI (3, 4). Apolipoprotein E polymorphism ε4 (APOE ε4) is a known genetic risk factor of MCI by causing abnormal amyloid aggregation (5, 6). Meanwhile, there are several studies have shown that sedentary behavior (SB) and longer sedentary time of older adults is very common (7, 8), and could increase the risk of cognitive decline (9-11). In addition, longitudinal studies have shown that SB could increase the risk of dementia (12, 13). Interestingly, a study of UK Biobank with 484169 participants and 56.5 years mean age showed that compared with APOE ε4 noncarriers, APOE ε4 carriers were more likely to see a decrease in AD incidence when physical activity (PA) is substituted for SB (12). However, SB is different from sedentary time, which is characterized by any waking activity that requires energy expenditure of 1.0 to 1.5 times the basal metabolic rate and a sitting or reclining posture, including television viewing, computer use, and sedentary time (8). Most studies consider sedentary behavior rather than specific sedentary time without considering genetic factors and the interaction with PA due to the availability of data or study design, and the outcome was usually dementia or cognitive decline rather than MCI (7-13).
In the context of the Tianjin Elderly Nutrition and Cognition (TENC) cohort study, the aim of this study was to explore the longitudinal associations between sedentary time and MCI, considering the APOE ε4 stratification and its interactions, and to identify a cut-off value for an increased risk of MCI. The purpose of this study was to provide a basis for specifying the sedentary time that increase the risk of MCI and to present evidence for optimizing healthy lifestyle related guidelines.

 

Methods

Study Participants

The present study used data from TENC cohort study, which is an ongoing population-based prospective study focusing on nutrition and cognitive health of older adults in rural areas of north China. Participants who were aged 60 years or over and were capable of walking, vision and hearing to complete the neuropsychological assessments were recruited from the Baodi District of Tianjin, China, from March 2018 to June 2021 and were followed-up from March 1, 2019 to November 30, 2022, with 3 visits and 3.11 years median follow-up duration, and the main outcome of each follow-up was the cognition of participants (3). Of the qualified individuals, 6542 participated in genotyping, 1610 participants were excluded from this analysis based on the following criteria: individuals who had a history of Parkinson’s disease (n=6), AD (n=4), stroke (n=361), or MCI (n=852); individuals with missing sedentary time related variables (n=387) (Figure 1). The remaining 4932 participants were included in the analysis. Salient characteristics of individuals included and excluded from the current study were largely comparable. The study protocol was approved by the ethics committee of Tianjin Medical University (approval number: TMUhMEC2018013), and all participants provided informed consent before participation. All of our procedures followed the Declaration of Helsinki.

Figure 1. Flowchart of study participants

Diagnosis of MCI

MCI was diagnosed by a modified version of the Petersen criteria (14): 1) subjective memory disorders over at least 6 months; 2) Mini-Mental State Examination (MMSE) score ≤17 points for illiteracy, ≤20 points for primary school, and ≤24 points for secondary education and above (15); 3) absence of dementia (Diagnostic and Statistical Manual of Mental Disorders, Fourth edition criteria), AD (National Institute of Neurological Disorders and Stroke Alzheimer Disease and Related Disorders Association criteria), psychiatric disorders, cerebral damage or other physical diseases resulting in cognitive impairment; 4) cognitive performance of 1.5 standard deviations (SDs) below the age-corrected (and education-corrected, where available) norms in at least one test in the neuropsychological battery; and 5) little or no difficulty in daily life activities, which measured by the Activities of Daily Living Scale (ADL) (<26 points) (16). Newly diagnosed MCI patients had to meet the above five criteria, and the diagnosis was based on expert consensus by a panel of physicians, neurologists, neuropsychologists, and psychiatrists (3).

Genotyping of APOE ε4 allele

Genomic DNA was extracted from fasting venous blood using the QIAamp DNA Mini Kit (Spark Jade Science Co., Ltd, Shandong, China). Genotypes were determined via the Custom Taqman SNP Genotyping Assay by sequencing rs429358 and rs7412 at exon 4 of the APOE gene, with the technical support of Shanghai OE Biotech Company.

Measurements of PA and sedentary time

A short version of the International Physical Activity Questionnaire (IPAQ) was used to collect information about physical activity (PA), which includes information on the number of minutes spent undertaking vigorous-intensity activities, moderate-intensity activities, walking, and sitting during the past week. Total PA was expressed in metabolic equivalent hours per week (MET-h/week), which was calculated by multiplying the hours per week spent undertaking vigorous, moderate, and walking activities with their corresponding MET coefficients (8.0, 4.0 and 3.3, respectively) and then summing the scores (17), and then divided in two categories: <23 and ≥23 METs-h/week (18). Sedentary time was obtained by standard question “Approximately how long do you sit each day?”.

Other variables

Demographic characteristics of the participants were obtained by a structured questionnaire, including age, sex, living alone, education levels, occupation, smoking status, alcohol consumption, sleep duration and medical history. During the clinical examination, participants’ height and weight were measured and their body mass index (BMI) (kg/m2) was calculated by dividing their weight (kg) by the square of the height (m2).

Statistical analysis

Kolmogorov-Smirmov normality test was used to test cumulative frequency distribution of continuous variables and were expressed as mean ± standard deviation (SD). Categorical variables were shown as frequencies and proportion percentages. Independent-samples t test was conducted for normal distribution variables, rank sum test for non-normal distribution variables and chi-square test for categorical variables to compare baseline characteristics between two trajectory groups. Cox proportional hazard regression was performed to explore the longitudinal association between sedentary time and MCI, where the hazard ratio (HR) and 95% confidence interval (CI) were calculated, and their relationship was further analyzed by APOE ε4 stratification, adjusted for sex, age, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities, sleep duration, occupation, baseline MMSE and ADL scores. In addition, considering the different prevalence of MCI in different age groups, we further performed age-stratified analyses, adjusted for sex, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities, APOE ε4 genotype, sleep duration, occupation, baseline MMSE and ADL scores. Considering the influence of PA intensity, we also stratified the sedentary time according to the median (2 hours/day) and explored joint effects of physical activity and sedentary on MCI by cox proportional hazard regression. In addition, we also explored interactions between APOE ε4, PA and sedentary time in both multiplicative scale, results were shown in β and 95% CI to reflect statistical interactions, and in additive scale, results were shown in relative excess risk due to interaction (RERI) and 95% CI to reflect biological interactions. We used rms package in R to conduct restricted spline curve for associations of sedentary time with MCI, taking into account APOE ε4, PA and age stratification. All analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) and R version 4.2.3 (R Foundation for Statistical Computing). Two-sided P Value < 0.05 was considered statistically significant.

 

Results

Sociodemographic characteristics of participants

Characteristics of the study participants are summarized in Table 1. A total of 4932 individuals were included, mean [SD] age was 67.85 [4.96] years, 2627 (53.3%) were females and 2305 (46.7%) males, with 740 newly onset MCI patients. Compared with non-MCIs, new MCI patients tended to be male, current smoker, drink alcohol, have an older age, higher education level, lower BMI, have hypertension, more likely to be APOE ε4 carriers, and have longer sedentary time (P values < 0.05). Besides, there were no significant differences of sleep duration, occupation, living alone, having diabetes, physical activities, MMSE and ADL scores between two groups (P values > 0.05).

Table 1. Characteristics of the study participants (n=4932)

MCI, mild cognitive impairment; BMI, body mass index; PA, physical activities; MMSE, Mini-Mental State Examination; ADL, Activities of Daily Living Scale.

 

Longitudinal association between sedentary time and MCI

Figure 2 showed that longer sedentary time was associated with higher risk of MCI for all participants in both unadjusted model (HR:1.087, 95%CI: 1.054, 1.122) and adjusted model (HR: 1.069, 95%CI: 1.034, 1.105). Besides, we found significant a synergistic interaction between sedentary time and APOE ε4 genotype (β:1.503, 95%CI: 1.163, 1.942, P<0.001) in multiplicative scale, but not in additive scale (RERI: -0.054, 95%CI: -0.587, 0.478). After APOE ε4 stratification, this association remained in APOE ε4 non-carriers in both unadjusted model (HR:1.095, 95%CI: 1.058, 1.133) and adjusted model (HR: 1.083, 95%CI: 1.045, 1.123), but not in APOE ε4 carriers in both unadjusted model (HR:1.040, 95%CI: 0.961, 1.126) and adjusted model (HR:1.004, 95%CI: 0.920, 1.097). After age stratification, this association remained in people with 60-64 years old in both unadjusted model (HR: 1.110, 95%CI: 1.051, 1.172) and adjusted model (HR: 1.081, 95%CI: 1.018, 1.149), also in people with 65 years old and above in both unadjusted model (HR: 1.080, 95%CI: 1.040, 1.122) and adjusted model (HR: 1.064 95%CI: 1.023, 1.108). Interestingly, we found a synergistic interaction between sedentary time and PA (β:1.495, 95%CI: 1.210, 1.846, P=0.001) in multiplicative scale, but not in additive scale (RERI: -0.120, 95%CI: -0.523, 0.284). The joint effects of sedentary time and PA on MCI risk was showed in Table 2. Results indicated that compared with individuals with higher PA and less sedentary time, individuals with higher PA and higher sedentary time (HR:1.346, 95%CI: 1.120, 1.619), individuals with less PA and less sedentary time (HR:1.268, 95%CI: 1.001, 1.608), and individuals with less PA and higher sedentary time (HR:1.495, 95%CI: 1.210, 1.846) were associated with a higher risk of MCI (P for trend < 0.001). The restricted cubic spline showed a linear relationship between sedentary time and incidence of MCI (P values for non-linearity were 0.773, 0.773, 0.764 and 0.672 in all participants, APOE ε4 stratification, PA stratification and age stratification, respectively.) in Figure 3. It exhibited a cut-off value of 3.03 hours/day in all participants (Figure 3A), APOE ε4 non-carriers (Figure 3B), people with higher PA (Figure 3C) and 65years old and above (Figure 3D), that is, the risk of MCI will increase when sedentary time exceeds 3.03 hours/day. Besides, a cut-off value of 2.08 hours/day for APOE ε4 carriers, 2.22 hours/day for people with lower PA, and 8.38 hours/day for people aged 60-64.

Figure 2. The longitudinal association between sedentary time and MCI

Model 1 adjusted for sex, age, BMI, education level, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities and APOE ε4 genotype. Model 2 additionally adjusted sleep duration, occupation, baseline MMSE and ADL scores based on model 1. Model 3 adjusted for sex, age, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone and physical activities. Model 4 additionally adjusted sleep duration, occupation, baseline MMSE and ADL scores based on model 3. Model 5 adjusted for sex, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities and APOE ε4 genotype. Model 6 additionally adjusted sleep duration, occupation, baseline MMSE and ADL scores based on model 5.

Table 2. Risk of MCI according to sedentary time and physical activities

Model adjusted for sex, age, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, APOE ε4 genotype, sleep duration, occupation, baseline MMSE and ADL scores.

Figure 3. Restricted spline curve for associations of sedentary time with MCI

(A) Model adjusted for sex, age, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities, APOE ε4 genotype, sleep duration, occupation, baseline MMSE and ADL scores. (B) Model adjusted for sex, age, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities, sleep duration, occupation, baseline MMSE and ADL scores. (C) Model adjusted for sex, age, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, APOE ε4 genotype, sleep duration, occupation, baseline MMSE and ADL scores. (D) Model adjusted for sex, education level, BMI, smoking, drinking alcohol, hypertension, diabetes, living alone, physical activities, APOE ε4 genotype, sleep duration, occupation, baseline MMSE and ADL scores.

 

In addition, we additionally performed logistic regression and its restricted spline curve to avoid that MCI occurrence would be affected by follow-up time, the results showed that people with longer sedentary time still had a higher risk of MCI (OR:1.104, 95%CI: 1.063, 1.146), and a linear relationship between sedentary time and MCI (P non-linearity=0.966) with the same cut-off value (Figure S1, Supplementary materials).

 

Discussion

This study revealed that long sedentary time was associated with higher MCI risk in all participants and APOE ε4 non-carriers. Besides, we also found a cut-off value of 3.03 hours/day of sedentary time for all participants, which means that the risk of MCI risk will increase when sedentary time exceeds 3.03 hours/day, and different cut-off values for diverse people after APOE ε4, PA and age stratifications. In addition, there were significant synergistic interactions between APOE ε4, PA and sedentary time.
Sedentary time has become a known modifiable determinant of health and an important predictor of healthy aging as society develops and lifestyle habits change. Recently, reviews have emerged indicating that long sedentary time may related to lower levels of cognitive function and an increased risk of cognitive decline (19-21). A cohort study of 484,169 participants from UK Biobank showed that the incidence of dementia was increased among participants with 5-8 h/day and >8 h/day of leisure-time SB compared to participants <5 h/day of leisure-time SB, and 1 SD increment of sedentary time (2.33 h/day) was strongly associated with a higher incidence of both dementia and mortality during a median 12.4 years of follow-up (12). In addition, this study also reported that APOE ε4 carriers were more likely to have reduced risk of AD and mortality when PA is substituted for SB. Similarly, a retrospective study from UK Biobank including 49,841 older adults presented that longer sedentary time was significantly associated with higher incidence of all-cause dementia (22). Furthermore, another cohort study of 90,320 participants from UK Biobank showed that longer sedentary time was related to a higher risk of dementia during a median follow-up of 6.9 years, and no additive and multiplicative relationship of PA and sedentary time to incident dementia was found (23). Another study of UK Biobank found that sedentary behavior revealed a J-shaped relationship with incidence of dementia (10). Also, a cohort from Seguimiento Universidad de Navarra reported interactions between SB and APOE ε4 (24). Interestingly, the LIFE randomized trial, a 24-month PA intervention vs. health education on cognitive outcomes in 1635 sedentary older adults, resulted in no improvements in global or domain-specific cognitive function, but participants over 80 years and those with lower baseline physical performance demonstrated that the PA group had better performance on executive function tasks than those in the health education group (25). Besides, another 24-month randomized PA intervention vs. health education intervention program in 26 sedentary older adults showed a hippocampal response to a long-term program of moderate-intensity PA (26). These suggested that SB had interactions with PA as well. The possible reasons for these interactions were that the effect of APOE ε4 has a greater impact on the risk of MCI than sedentary time, that is, genetic risk was more effective than environmental factors on MCI incidence. Besides, regular PA has been proved to reduce inflammation and reduce brain oxidative stress by improving the expression of several antioxidant enzymes (12). Naturally, longer sedentary time with less PA may be associated with a significant increase in MCI. Notably, we have not found statistical differences in additive scale of the interaction between PA and sedentary time, this probably affected by follow up duration. It’s worth noting that most cohort studies were about public databases and this may cause some bias. Meanwhile, several cross-sectional studies have also reported that longer sedentary time could contribute to higher risk of cognitive decline and brain structure change (27-30).
However, different types of SBs may be differentially associated with health outcomes relevant to older adults, and some may even be beneficial for cognitive function, such as reading and work-related SB (31-33). Therefore, different domains of SBs could influence the association between sedentary time and MCI, which should be refined in future studies. Our results were consistent with these studies, and we found a cut-off value of 3.03 hours/day of sedentary time by restricted spline curve instead of manually classification. Meanwhile, we found different values after stratifications, APOE ε4 carriers, people with lower PA and higher age had a small cut-off value compared with APOE ε4 non-carriers, people with higher PA and lower age. This may be caused by their interactions.
Our findings have clinical and public health significance for the primary prevention of MCI. Especially for APOE ε4 non-carriers, reducing sedentary time has a greater effect on preventing MCI. This study has several strengths, we used strict and standardized protocols for data collection and adjusted possible confounding factors, which could reduce confounding bias to some extent. However, there are still some limitations of this study that need to be pointed out. First, information of sedentary time and PA were collected by questionnaire or standard questions and they were not randomly assigned as genetic factors. Second, despite adjusting for known potential factors, the possibility of unmeasured confounders remains. Third, the sample of current study was from the TENC cohort, therefore, further studies are needed to determine the extent of extrapolation of these results.
In summary, long sedentary time (≥3.03 hours/day) could increase MCI risk of community-dwelling older adults, especially in APOE ε4 non-carriers. In addition, synergistic interactions were found between APOE ε4, PA and sedentary time. These findings could contribute to the prevention of early state of dementia and the optimization of healthy lifestyle related guidelines.

 

Acknowledgements: We greatly appreciate the co-operation and participants of teacher, nurses, doctors, students and participants.

Funding: This work was supported by grants from the National Natural Science Foundation of China (grant number: 81730091), National Key R&D Program of China (grant number: 2022YFC2010103) and Tianjin Key Medical Discipline (Specialty) Construction Project (grant number: TJYXZDXK-065B). The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or in the review or approval of the manuscript.

Conflict of Interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

 

SUPPLEMENTARY MATERIAL

 

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