Interactions Between Handgrip Strength and Serum Folate and Homocysteine Levels on Cognitive Function in the Elderly Chinese Population

Abstract

Background:

Handgrip strength (HGS) and serum folate and homocysteine (Hcy) levels were associated with cognitive function. However, little was known whether there were interactions between HGS and serum folate and Hcy levels on cognitive function.

Objective:

To examine the interactions between HGS and serum folate and Hcy levels on cognitive function.

Methods:

This study analyzed the baseline data of the Tianjin Elderly Nutrition and Cognition Cohort study. All participants aged ≥60 years were potential eligible. HGS was measured using a grip strength dynamometer. Serum folate and Hcy levels were assayed using standard laboratory protocol. A Mini-Mental State Examination was used to assess cognitive function. Linear regressions were employed to examine the interactions between HGS and serum folate and Hcy levels on cognitive function.

Results:

4,484 participants were included in this study. There were interactions between HGS and serum folate and Hcy levels on cognitive function. Furthermore, subjects with strong HGS and sufficient folate level had the best cognitive function (β= 2.018), sequentially followed by those with strong HGS and insufficient folate level (β= 1.698) and with poor HGS and sufficient folate level (β= 0.873). Similarly, cognitive function was ranked in the descending order of subjects with strong HGS and normal Hcy level (β= 1.971), strong HGS and high Hcy level (β= 1.467), and poor HGS and normal Hcy level (β= 0.657).

Conclusion:

There were interactions between HGS and serum folate and Hcy levels on cognitive function. However, the temporal associations cannot be examined in a cross-sectional study. Further cohort study should be conducted to confirm these associations in the future.

Keywords

Alzheimer’s disease cognitive function handgrip strength serum folate serum homocysteine

INTRODUCTION

Cognitive function reflects an individual’s ability to attain information and knowledge, including memory, attention, and language [1]. The individuals with cognitive decline will suffer from poor independence, quality of life, and daily life functional abilities [2]. Cognitive function will decline with aging, and older people may suffer from cognitive impairment, which is characterized by acquired impairment of intellectual and memory functions [3]. Without effective interventions, appropriately 10% to 15% of individuals with cognitive impairment will develop to Alzheimer’s disease dementia per year, which is the most common cause of acquired cognitive impairment [4, 5]. Worldwide, the number of people with dementia in 2019 was estimated to be 50 million, and it will increase to 152 million by 2050 [6]. Correspondingly, the annual cost of dementia is nearly one trillion dollar, and it will double by 2030 [6]. Since the number of older adults aged ≥60 years was approximately 841 million and will increase to two billion by 2050, the coverage of people affected by dementia, along with its huge disease burden, will be a great challenge in the future [7]. Therefore, it is a growing urgency to identify modifiable risk factors and predictors for cognitive function.

Previous studies have reported that handgrip str-ength (HGS) was positively associated with cognitive function [8, 9]. This may be due to the fact that HGS and cognitive function shared the similar age-related neurologic deterioration [10]. Up to date, many studies have found that gait speed, HGS, and balance were associated with cognitive function in the elderly people [10 –14]. Meanwhile, as an important element of the nervous system activities, serum folate was suggested to be associated with cognitive function [3 , 16]. Furthermore, as an intermediate of the methionine cycle, elevated homocysteine (Hcy) levels were associated with cognitive decline [17, 18]. A previous study found that serum folate levels were significantly associated with grip strength and physical performance [19]. Since folate acts in the remethylation cycle that converts homocysteine to methionine, a higher serum homocysteine level could decrease physical performance [20]. Therefore, it was hypothesized that there might be interplay relationships between HGS and serum folate and Hcy levels on cognitive function. To our knowledge, little has been done in this field.

Therefore, the aims of this study were to examine the mutual effects between HGS and serum folate and Hcy levels on cognitive function, and to assess if serum folate and Hcy levels modified the associations of HGS with cognitive function. As a result, it was expected that this study would help to demonstrate how co-existence of HGS and serum folate and Hcy levels affect cognitive function, which would provide evidence for interventions in preserving muscle strength and improving cognitive function with aging.

METHODS

Study design and population

This study analyzed a cross-sectional leveraged data collected at baseline from the Tianjin Elderly Nutrition and Cognition Cohort (TENCC) study (Clinical Trials Registration Identifier: ChiCTR2000034348), an ongoing China elderly population-based prospective cohort study focused on the relationship between nutrition and cognitive health. Briefly, participants were recruited from Baodi district of Tianjin (China), who were sufficiently competent in walking, vision, and hearing to complete assessments, and were aged 60 years or older at enrollment from March 2018 to June 2019. A random stratified cluster sample was employed to select three communities in Baodi, where a total of 5,320 eligible subjects were recruited at baseline. All participants were interviewed by trained health professionals to obtain information on demographic and socioeconomic profiles, dietary intakes, HGS, cognitive function, and blood samples. This study was approved by the institutional Review Board of Tianjin Medical University. All participants provided informed consent.

In this study, all participants aged ≥60 years were eligible. Inclusion criteria were: those who had complete demographic data, and those who completed the cognitive tests. Individuals were excluded if they reported extreme data or had missing data on in the interesting variables (n = 577); if they had cerebrovascular diseases, such as stroke, apoplexy, or brain cancer, and gastric tumors (n = 148); if they had mental diseases (n = 0); if they had any surgery in the last 3 months, or if they could not complete the HGS tests due to arthritis or pain in the arm or leg (n = 111). Finally, a total of 4484 subjects were included in this study.

Handgrip strength

HGS was measured in the dominant and non-dominant arms using a grip strength dynamometer (Sammons Preston Rolyan, Bolingbrook, IL, USA). Before the practice trial, interviewers explained the protocols and fit the dynamometer to the hand size according to each participant. And participants were required to try practice the trial to be proficient in operation. During the tests, each participant was asked to squeeze the dynamometer with maximal effort in a standing position. Meanwhile, their arm should be at their side and elbow flexed at 90°, as well as the shoulder, forearm, and wrist should be in neutral positions. The handgrip strengths of the left and right hands were measured twice, and the average of dominant hand was used for this study. HGS < 26 kg and < 16 kg were considered as poor for males and females, respectively [21].

Serum folate and Hcy levels

The concentration of serum folate was assayed using Auto-chemiluminescence immunoassay analyzer (IMMULITE 2000 XPi, New Jersey, USA). When the concentration of serum folate was lower than 6 ng/ml, folate insufficiency was identified [19]. Serum Hcy concentration was assayed using Auto-Chemistry Analyzer (CS- T300, DIRUI, Changchun, China). Hyperhomocysteinemia was defined as Hcy > 15μmol/L [22].

Cognitive function

In this study, the Mini-Mental State Examination (MMSE) was used to assess the cognitive function, which has been used in previous studies and confirmed to be valid [23]. The cognitive screening consisted of 5 items: 1) immediate recall of a 3-word list (one score per word), 2) date and site (a total score of 10), 3) serial seven subtractions (one score for one time, and in total 5 times), 4) delayed recall of a 3-word list (one score per word), and 5) language and vision (a total score of 9). The sum of cognitive score is 30. A higher cognitive score represents better cognition.

Covariates

Physical indicators, such height and weight, were measured following standardized protocols. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Normal weight was defined as a BMI < 24 kg/m², and obesity was defined as a BMI ≥24 kg/m² [24]. The married status, education levels, family income levels, smoking, and drinking were collected using a valid questionnaire. Age was categorized as 60–69 years and 70–90 years subgroups. Married status was categorized as unmarried, married, divorced, and widowed. Education levels were categorized as primary school or below, middle school, and college or above. Family income levels were categorized as ≤3000 Yuan, 3000–5000 Yuan, 5000–10000 Yuan, and ≥10000 Yuan. Both smoking and drinking were categorized as Yes or No. The history of diabetes, hypertension, and cardiovascular diseases were collected via a similar question: Have you ever been diagnosed as diabetes, hypertension, or cardiovascular diseases by a physician? They were categorized as Yes or No. The Food Frequency Questionnaire was used to collect the data of dietary intake for each subject, which was used to calculate the folate level of dietary intake.

Statistical analysis

Kolmogorov-Smirnov test was used to test the distributions of continuous variables. Given the non-normality of continuous variables, median and interquartile range were used to describe the distributions of continuous variables, and frequencies and percentages were used for categorized variables. Linear regressions were employed to examine the associations of HGS and serum folate and Hcy levels with cognitive function, as well as the interactions between HGS and serum folate and Hcy levels on cognitive function. Since there were associations of age, sex, BMI, married status, education levels, family income levels, smoking, drinking, and history of diabetes, hypertension, or cardiovascular diseases with cognitive function in a previous study of our team, which analyzed the same original data as this study [25], these factors were adjusted in multivariate models. Given folate level of dietary intake was associated clinically with serum folate, it was also adjusted in sensitivity analysis. The associations of HGS and serum folate and Hcy levels with cognitive function were further analyzed stratified by age and sex. Furthermore, since observations with missing data were removed in this study, the analyzed data was a subset of the original data. In order to examine the impact of missing data, sensitivity analysis was used to compare the differences between the analyzed data and the original data. Meanwhile, sensitivity analysis was further conducted to examine the interactions between HGS and serum folate and Hcy levels on cognitive function with additionally adjusting for folate level of dietary intake. Furthermore, since MMSE score was non-normality, the results of linear regression models with MMSE score as response variable might be biased. Therefore, logistic regression was conducted to explore the impact of the non-normality of MMSE score in sensitivity analysis, in which MMSE score was dichotomized into normal cognitive function and mild cognitive impairment according to a previous study [25]. All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA), and with a two-tailed p ≤0.05 indicating statistical significance.

RESULTS

The characteristics of all participants

In total, 4,484 participants were included in the final analyses. The median and interquartile range of age was 67.00 (64.00, 71.00) years, and the median and interquartile range of MMSE was 26.00 (23.00, 28.00). The proportion of males was 44.58%. The characteristics of all participants are shown in Table 1.

Table 1

The characteristics of all subjects (N = 4,484)

Characteristics	Numbers	Percentages (%)
Age (y)
60–69	3,002	66.95
70–90	1,482	33.05
BMI
Normal weight	1,408	31.40
Obesity	3,076	68.60
Handgrip strength
Poor	2,967	66.17
Strong	1,517	33.83
Serum folate
Insufficient	2,075	46.28
Sufficient	2,409	53.72
Serum Hcy
Normal	2,955	65.90
High	1,529	34.10
Cognitive function
Normal	3,924	87.51
MCI	5,60	12.49
Sex
Males	1,999	44.58
Females	2,485	55.42
Married status
Unmarried	42	0.94
Married	3,935	87.76
Divorced	77	1.72
Widowed	430	9.59
Education levels
Primary school or below	1,288	28.72
Middle school	2,903	64.74
College or above	293	6.53
Monthly family income levels
≤3000 Yuan	3,235	72.15
3000–5000 Yuan	643	14.34
5000–10000 Yuan	496	11.06
≥10000 Yuan	110	2.45
Smoking
No	2,851	63.58
Yes	1,633	36.42
Drinking
No	1,023	22.81
Yes	3,461	77.19
History of hypertension
No	2,546	56.78
Yes	1,938	43.22
History of diabetes
No	3,875	86.42
Yes	609	13.58
Cardiovascular disease
No	3,902	87.02
Yes	582	12.98

BMI, body mass index; MMSE, Mini-Mental State Examination; Hcy, homocysteine; MCI, mild cognitive impairment.

The associations of HGS and serum folate and Hcy levels with cognitive function

Table 2 displays the associations of HGS and serum folate and Hcy levels with cognitive function. In the total population, HGS and serum folate and Hcy levels were separately analyzed, and all index were found to be associated with cognitive function. Furthermore, increased HGS and serum folate level were associated with better cognitive function (β= 0.043, 95% CI: 0.032∼0.054; and β= 0.058, 95% CI: 0.031∼0.084, respectively). However, serum Hcy level was inversely associated with cognitive function (β= –0.024, 95% CI: –0.038∼ –0.009). When stratified by sex, the results of males and females were similar to the results of total population.

Table 2

The associations of HGS and serum folate and Hcy levels with cognitive function

	Model 1^⋇			Model 2^#
	β	p	95% CI	β	p	95% CI	Standard β
Total (N = 4,484)
HGS	0.043	< 0.001	0.032∼0.054	0.043	< 0.001	0.032∼0.054	0.524
Serum folate	0.058	< 0.001	0.031∼0.084	0.050	< 0.001	0.023∼0.077	0.215
Serum Hcy	–0.024	0.001	–0.038∼–0.009	–0.017	0.025	–0.032∼–0.002	–0.133
Males (N = 1,999)
HGS	0.024	< 0.001	0.015∼0.034	0.024	< 0.001	0.015∼0.034	0.297
Serum folate	0.047	0.011	0.011∼0.082	0.037	0.048	0.001∼0.073	0.158
Serum Hcy	–0.019	0.008	–0.034∼–0.005	–0.016	0.033	–0.031∼–0.001	–0.125
Females (N = 2,485)
HGS	0.122	< 0.001	0.095∼0.148	0.121	< 0.001	0.094∼0.147	1.478
Serum folate	0.068	< 0.001	0.031∼0.104	0.058	0.002	0.021∼0.095	0.249
Serum Hcy	–0.045	0.002	–0.073∼–0.016	–0.029	0.049	–0.057∼–0.001	–0.225

^divonx;In model 1, handgrip strength, serum folate, and homocysteine were analyzed separately. In total population, age, sex, body mass index, married status, education levels, monthly family income levels, smoking, drinking, diabetes history, hypertension history, and cardiovascular disease history were adjusted. In males and females, age, body mass index, married status, education levels, monthly family income levels, smoking, drinking, history of diabetes, history of hypertension, and cardiovascular disease were adjusted. ^#In model 2, handgrip strength, serum folate, and homocysteine were analyzed simultaneously. In total population, age, sex, body mass index, married status, education levels, monthly family income levels, smoking, drinking, diabetes history, hypertension history, and cardiovascular disease history were adjusted. In males and females, age, body mass index, married status, education levels, monthly family income levels, smoking, drinking, history of diabetes, history of hypertension, and cardiovascular disease were adjusted.

When HGS and serum folate and Hcy levels were analyzed simultaneously, the results were consistent with those as they were analyzed separately (β= 0.043, 95% CI: 0.032∼0.054; β= 0.050, 95% CI: 0.023∼0.077; and β= –0.017, 95% CI: –0.032∼ –0.002, respectively). Similarly, the results stratified by sex were comparable with the results of total population. Moreover, when HGS and serum folate and Hcy levels were analyzed simultaneously, the association of HGS with cognitive function was the strongest in the total population (standardized β= 0.524), and followed by serum folate (standardized β= 0.215) and then by serum Hcy (standardized β= –0.133). Similar results were observed in both males and females.

Interactions between HGS and serum folate and Hcy levels on cognitive function

There were significant interactions between HGS and serum folate and Hcy levels (p = 0.035, and 0.001, respectively) (Table 3). Therefore, the simultaneous associations of HGS and serum folate and Hcy levels with cognitive function were further analyzed.

Table 3

The interactions between HGS and serum folate and Hcy levels on cognitive function^divonx;

HGS	β	p	95% CI
Serum folate	–0.003	0.035	–0.005∼–0.001
Serum Hcy	0.002	0.001	0.001∼0.003

^divonx;age, sex, body mass index, married status, education levels, monthly family income levels, smoking, drinking, history of diabetes, history of hypertension, and cardiovascular disease were adjusted.

Table 4 shows simultaneous associations of HGS and serum folate and Hcy levels with cognitive function. In model 1, compared to subjects with poor HGS and insufficient folate, subjects with strong HGS and sufficient folate level had the best cognitive function (β= 2.018, 95% CI: 1.681–2.354), sequentially followed by subjects with strong HGS and insufficient folate level (β= 1.698, 95% CI: 1.360–2.036) and subjects with poor HGS and sufficient folate level (β= 0.873, 95% CI: 0.501–1.245). Similarly, subjects with strong HGS and normal Hcy level had the best cognitive function (β= 1.971, 95% CI: 1.621–2.321), sequentially followed by subjects with strong HGS and high Hcy level (β= 1.467, 95% CI: 1.085–1.848) and subjects with poor HGS and normal Hcy level (β= 0.657, 95% CI: 0.275–1.040).

Table 4

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function

Models	HGS	Biomarkers	β	p	95% CI
Model 1^⋇		Serum folate
	Poor	Insufficient	Ref
	Poor	Sufficient	0.873	< 0.001	0.501∼1.245
	Strong	Insufficient	1.698	< 0.001	1.360∼2.036
	Strong	Sufficient	2.018	< 0.001	1.681∼2.354
Model 2^⋇		Serum Hcy
	Poor	High	Ref
	Poor	Normal	0.657	0.001	0.275∼1.040
	Strong	High	1.467	< 0.001	1.085∼1.848
	Strong	Normal	1.971	< 0.001	1.621∼2.321

^divonx;In models 1 and 2, age, sex, body mass index, married status, education levels, monthly family income levels, smoking, drinking, history of diabetes, history of hypertension, and cardiovascular disease were adjusted.

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function stratified by age

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function stratified by age are shown in Fig. 1. Both in the 60–69 years and 70–90 years, the simultaneous associations of HGS and serum folate and Hcy levels with cognitive function were similar with those in total population, except in the subjects aged 70–90 years with poor HGS and normal serum Hcy level (p =0.318). With subjects having poor HGS and insufficient folate as the reference, subjects with strong HGS and sufficient serum folate had better cognitive function in the 60–69 years subgroup (β= 1.855, 95% CI:1.435∼2.276) and in the 70–90 years subgroup (β= 2.436, 95% CI: 1.849∼3.024). Furthermore, the simultaneous association of HGS and serum folate level with cognitive function was more obvious in the 70–90 years versus 60–69 years subgroups (β= 2.436 versus 1.855).

Fig. 1

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function stratified by age. (The sample sizes of 60–69 years and 70–90 years were 3,002 and 1,482, respectively; Sex, body mass index, married status, education levels, family income levels, smoking, drinking, history of diabetes, history of hypertension, and cardiovascular disease were adjusted).

The simultaneous association of HGS and serum Hcy level with cognitive function suggested that subjects with normal serum Hcy level and strong HGS performed the best cognitive function in both 60–69 years and 70–90 years subgroups (β= 2.144, 95% CI: 1.685∼2.603; and β= 2.006, 95% CI: 1.430∼2.583, respectively). Moreover, the simultaneous association of HGS and serum Hcy level with cognitive function was more obvious in the 60–69 years versus 70–90 years subgroups (β= 2.144 versus 2.006).

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function stratified by sex

When stratified by sex, the results were comparable with those in total population. Subjects with strong HGS and sufficient serum folate level performed the best cognitive function in both males and females (β= 1.387, 95% CI: 0.979∼1.796; and β= 2.515, 95% CI: 2.012∼3.018, respectively). Meanwhile, the coexistence of strong HGS and normal serum Hcy level was associated with the best cognitive function in both males and females (β= 1.308, 95% CI: 0.894∼1.722; and β= 2.605, 95% CI: 2.073∼3.137, respectively). Furthermore, the simultaneous association of HGS and serum folate and Hcy levels with cognitive function was more obvious in females (β= 1.387 versus 2.515, and β= 1.308 versus 2.605, respectively) (Fig. 2).

Fig. 2

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function stratified by sex. (The sample sizes of males and females were 1,999 and 2,485, respectively; age, body mass index, married status, education levels, family income levels, smoking, drinking, history of diabetes, history of hypertension, and cardiovascular disease were adjusted).

Sensitivity analysis

Due to the missing data, the sample used for the current analysis differed from the ongoing China elderly population-based cohort study. However, no significant differences were found between the original sample (n = 5320) and the sample of this study (n = 4484) with regard to age (p = 0.396) and sex (p = 0.897). Furthermore, when adjusting for folate level of dietary intake, the simultaneous associations of HGS and serum folate and Hcy levels with cognitive function did not substantially change (Table 5).

Table 5

The simultaneous associations of HGS, serum folate and Hcy levels with cognitive function with additionally adjusting for folate level of dietary intake in the sensitivity analysis (N = 3,278)

Models	HGS	Biomarkers	β	p	95% CI
Model 1^⋇		Serum folate
	Poor	Insufficient	Ref
	Poor	Sufficient	0.784	< 0.001	0.377∼1.191
	Strong	Insufficient	1.681	< 0.001	1.308∼2.054
	Strong	Sufficient	1.892	< 0.001	1.522∼2.262
Model 2^⋇		Serum Hcy
	Poor	High	Ref
	Poor	Normal	0.746	0.001	0.329∼1.162
	Strong	High	1.528	< 0.001	1.111∼1.944
	Strong	Normal	1.964	< 0.001	1.583∼2.344

Meanwhile, since MMSE score was non-norma-lity, the results might be biased with MMSE score as the response variable of linear regression model. When MMSE score was dichotomous, the results were consistent with the main results of linear regression models (Table 6).

Table 6

The simultaneous associations of HGS, serum folate and Hcy levels with cognitive function which was identified as binary variable in the sensitivity analysis (N = 4,484)

Models	HGS	Biomarkers	OR	p	95% CI
Model 1^⋇		Serum folate
	Poor	Insufficient	Ref
	Poor	Sufficient	0.640	0.023	0.493∼0.831
	Strong	Insufficient	0.406	0.001	0.312∼0.528
	Strong	Sufficient	0.306	< 0.001	0.235∼0.399
Model 2^⋇		Serum Hcy
	Poor	High	Ref
	Poor	Normal	0.666	0.020	0.511∼0.869
	Strong	High	0.444	0.020	0.331∼0.596
	Strong	Normal	0.316	< 0.001	0.242∼0.412

DISCUSSION

This study was designed to investigate the mutual effects of HGS and serum folate and Hcy levels on cognitive function. The results implied that HGS and serum folate and Hcy levels were significantly associated with cognitive function, and their effect sizes were listed as follows: HGS > serum folate level > serum Hcy level. With subjects having poor HGS and insufficient folate or high serum Hcy level as the references, better cognitive function was found in the subjects with strong HGS and sufficient serum folate level and in those with strong HGS and normal serum Hcy level. Furthermore, the simultaneous association of HGS and serum folate level with cognitive function was more obvious in females aged 70–90 years. However, the simultaneous association of HGS and serum Hcy level with cognitive function was more obvious in females aged 60–69 years.

Previous studies found that HGS was an effective predictor of cognitive decline [26 –28]. The potential mechanisms may be explained by the fact that cognitive function and HGS commonly relied on the central nervous system [29, 30]. Thus, they shared the same cause. Additionally, white matter integrity might be a common neuropathological cause of cognitive impairment and HGS [9, 31]. Moreover, another common cause might be the aging process, including brain circuitry, brain pathology, and loss of molecular fidelity [32 –34]. Furthermore, the association of HGS with cognitive function was the strongest among three interesting indicators, which was consistent with previous studies [35, 36].

In this study, the significant interactions were found between HGS and serum folate and Hcy levels. Furthermore, better cognitive function was found in the subjects with strong HGS and sufficient folate. A few studies have reported that serum folate status was associated with the muscle strength in the older people and suggested that a lower level of folate was associated with poorer physical performance [19]. The potential mechanisms might be due to folate-specific activities, including neurotransmitter synthesis, myelination, synthesis of DNA and protein, DNA methylation and epigenetic regulation [20, 37]. Therefore, it is possible that mutual relationships exited between HGS and serum folate level.

The simultaneous associations of HGS and serum Hcy level with cognitive function suggested that the coexistence of strong HGS and normal serum Hcy level was associated with better cognitive function. Previous study has found that elevated serum Hcy level was associated with a lower HGS [38]. The association of HGS with serum Hcy level was regulated by the protein homocysteinylation, which is the post-translational acylation of free amino groups mediated by Hcy thiolactone [39]. Through the homocysteinylation of protein lysine in serum, Hcy thiolactone reacts with proteins and causes the toxicity via the oxidative damage to proteins, and then leads to muscle weakness and atrophy [40]. Therefore, elevated serum Hcy level followed by poor HGS was associated with serious cognitive function.

The simultaneous associations of HGS and serum folate and Hcy levels with cognitive function was more obvious in females than males. These might be explained by the single associations of HGS and serum folate and Hcy levels with cognitive function. A previous study reported that serum folate had a greater effect on muscle strength in females than males [19]. Meanwhile, HGS was more often associated with cognitive function and a wider number of domains in cognitive tests in females [12]. Therefore, there might be sex disparities in the associations of HGS and serum folate and Hcy levels with cognitive function.

Meanwhile, the simultaneous association of HGS and serum folate level with cognitive function was more obvious in subjects aged 70–90 years than in those aged 60–69 years. However, the simultaneous association of HGS and serum Hcy level with cognitive function was more obvious in subjects aged 60–69 years than in those aged 70–90 years. The underlying mechanisms under these associations were still unknown. It was speculated that it was related with rate of cognitive decline with age. It was documented that rate of cognitive decline was steeper in older individuals [41]. Therefore, rate of cognitive decline in subjects aged 70–90 years was steeper than that in subjects aged 60–69 years. It was established that HGS decreased over age in subjects aged 60 years and older [42]. Since serum folate level could retard cognitive decline [3], the simultaneous association of HGS and serum folate level with cognitive function was more obvious in subjects with steeper rate of cognitive decline. Contrarily, serum Hcy level could accelerate cognitive decline [17]. Therefore, the simultaneous association of HGS and serum Hcy level with cognitive function was more obvious in subjects with less steeper rate of cognitive decline. The underlying mechanisms under these associations need further be studied from laboratory research in the future.

Strengths and limitations

To our knowledge, this is the first study to examine the mutual association of HGS a nd serum folate and Hcy levels with cognitive function. As a result, this study will provide new evidence and insights for the prevention of cognitive decline, even dementia. Moreover, whether serum folate and Hcy levels modified the associations of HGS with cognitive function was presented in this study. Thus, personalized interventions and treatments could be provided for individuals with cognitive decline in terms of their serum folate and Hcy levels. Meanwhile, the limitations of this study should be stated. First, this was a cross-sectional study, which was unable to establish the causal relationship between exposures and outcomes of interest. Second, the underlying mechanisms under the mutual effects between HGS and serum folate and Hcy levels on cognitive function failed to be fully explained. Therefore, further intervention studies are needed in the future. Third, only MMSE score was used to evaluate cognitive function. There might be measurement bias. Fourth, although the information of dietetic intakes was collected at baseline, only the frequency of dietetic intakes was recorded. Furthermore, there were some missing data of dietetic intakes. Therefore, it was difficult to calculate the intake of nutrients and adjust for the dietetic intakes in linear regressions.

CONCLUSIONS

There were significant associations of HGS and serum folate and Hcy levels with cognitive function, and the effects of them on cognitive function were HGS > serum folate > serum Hcy. Meanwhile, the interactions between HGS and serum folate and Hcy levels were observed. Better cognitive function was observed in the subjects with strong HGS and sufficient serum folate level, as well as in those with strong HGS and normal serum Hcy level. The interactions between HGS and serum folate and Hcy levels on cognitive function were more impressive in females. Therefore, this study provided some suggestions on the associations of HGS and serum folate and Hcy levels with cognitive function in the older population. For clinicians, patients with poor HGS, insufficient serum folate, and high Hcy levels might be considered as high risk of cognitive decline. Meanwhile, there might be association of neurodegeneration with muscle attenuation. However, the temporal associations cannot be examined in a cross-sectional study. Further cohort studies should be conducted to confirm these associations in the future.

Footnotes

ACKNOWLEDGMENTS

We greatly appreciate the co-operation and participants of teacher, nurses, doctors, students and par-ticipants. This work was supported by grants from the National Natural Science Foundation of China (grant number: 81730091).

Authors’ disclosures available online ().

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