The Impact of Vitamin D and Cognitive Function on All-Cause Mortality Among Older Chinese Adults: A Population-based Longitudinal Study

doi:10.21203/rs.3.rs-1750232/v1

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The Impact of Vitamin D and Cognitive Function on All-Cause Mortality Among Older Chinese Adults: A Population-based Longitudinal Study

https://doi.org/10.21203/rs.3.rs-1750232/v1

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Background

While both vitamin D deficiency and cognitive impairment have individually been linked to a greater risk of all-cause mortality, the combined effects of these two different conditions have not previously been explored in this context. We aimed to investigate the combined impact of vitamin D levels and cognitive impairment on all-cause mortality in older adults.

Methods

Analyzed data were collected from community-dwelling adults ≥ 65 years of age that were enrolled in the Chinese Longitudinal Healthy Longevity Survey for whom follow-up data were available over a 7-year period (n = 2,154). The Mini-Mental Status Examination (MMSE) was used to detect cognitive impairment, while plasma 25-hydroxyvitamin D (25(OH)D) concentrations were used to measure vitamin D concentrations. The associations between baseline cognitive function and vitamin D were assessed using bivariate logistic regression models, while the relationships between vitamin D levels, cognitive function, and all-cause mortality were assessed with Cox proportional hazards models. Joint effect testing to explore interactions between vitamin D levels and cognitive function.

Results

Of the included study participants, 839 (39.0%) died over the course of follow-up. Individuals in the lowest 25(OH)D quartile exhibited a 1.61-fold higher risk of cognitive impairment as compared to participants within the highest quartile. A negative dose-response relationship was observed between 25(OH)D levels and odds of all-cause mortality. Similarly, cognitive impairment was significantly related to mortality risk (HR 1.75, 95% CI: 1.49 to 2.06). Relative to participants with normal cognition in the highest 25(OH)D quartile, a negative dose-response relationship was observed between the levels of 25(OH)D and the odds of all-cause mortality. Moreover, the interaction between 25(OH)D levels and cognitive function was found to be significant with respect to the risk of mortality (P for interaction < 0.001).

Conclusions

These data suggest that lower plasma 25(OH)D concentrations are related to the development of cognitive impairment, while 25(OH)D and cognitive impairment exhibit an additive combined effect on all-cause mortality among older Chinese adults.

vitamin D

cognition

elderly

mortality

cohort study

Cognitive impairment is an adverse neurological state that grows increasingly prevalent with advanced age and is defined as the impairment or disruption of one or more key cognitive functions, including learning, attention, memory, or decision-making [1]. The incidence rates of dementia and mild cognitive impairment (MCI) among Chinese adults 60 years of age or older were estimated to be 6% and 15.5%, respectively, in one large study of a nationally representative population [2]. Over 50% of patients with MCI progress to a diagnosis of dementia within a 5-year period [3]. Critically, cognitive impairment has been linked to higher odds of mortality [4–6], and this relationship is more pronounced in individuals with comorbid chronic diseases and conditions, including cardiovascular disease [7, 8], diabetes [9], frailty [10], and kidney failure [11]. It is thus vital that factors influencing the association between cognitive impairment and mortality be defined.

Older adults who suffer from dementia or cognitive impairment engage in lower levels of physical activity [12, 13] and take in less vitamin D than do healthy individuals [14]. As such, cognitively impaired adults may be more likely to develop a vitamin D deficiency, which is associated with a higher risk of overall mortality [7, 15, 16]. Screening for vitamin D deficiencies and corresponding vitamin supplementation is highly economical. However, no prior studies have established whether a combination of cognitive impairment and vitamin D deficiency is associated with an elevated risk of all-cause mortality. If such a relationship were to exist, then it would have the potential to aid in the care of cognitively impaired older adults to prolong survival and improve quality of life.

This study assessed the association between all-cause mortality and the combined effects of vitamin D deficiency and cognitive impairment using prospective data derived from a nationally representative population of Chinese adults 65 years of age or older. For this analysis, we hypothesized that lower levels of vitamin D would correspond to a higher risk of mortality among cognitively impaired older adults. The results of this analysis have the potential to inform future interventional efforts aimed at preventing premature death among older adults affected by both vitamin D deficiency and cognitive impairment.

Study Participants

Data used in this study were derived from the ongoing, prospective, multidisciplinary Chinese Longitudinal Healthy Longevity Survey (CLHLS), which was developed to explore health and longevity-related factors among elderly Chinese individuals [17,18]. Baseline CLHLS surveys were performed in 1998, with follow-up having been conducted every 2, 3, or 4 years thereafter. Biomarker-based studies have been performed every 3-4 years since 2008 in 8 longevity regions.

Participants in the current study were recruited from the 2011-2012 and 2014 CLHLS biomarker sub-study waves, with follow-ups having been conducted in 2014 and 2018. Individuals eligible for inclusion in this study were adults ≥65 years of age for whom baseline biomarker and cognitive assessment data were available. Participants lost to follow-up were excluded from these analyses. In total, 2,154 participants were included in this analysis for whom data were available to analyze the effects of vitamin D levels and cognitive impairment on all-cause mortality. A patient inclusion flowchart is shown in Supplementary Figure S1.

Outcomes

Participant mortality was recorded during the CLHLS 2014 and 2018 follow-up waves. The date of death was determined based on death certificates or reports from next of kin or neighborhood committees, with survival being calculated based on the interval between the initial interview and the date of death. Surviving participants at the most recent follow-up were treated as censored observations, with censoring time being measured as the interval from the first interview to the most recent follow-up.

Cognitive function analyses

The Chinese version of the Mini-Mental State Examination (MMSE), which is the Chinese-adapted version of the international MMSE survey (Supplementary Table S1), was used to assess participant cognitive function in this study. The validity and reliability of the Chinese version of this survey have been documented previously [4, 19]. The MMSE is composed of 6 dimensions (time/place orientation, word registration, attention and calculation, memory, visual construction, and language). The total possible score is between 0 and 30. MMSE score thresholds for cognitive impairment were adjusted for level of education such that cognitively impaired individuals were those meeting the following criteria: (1) illiterate individuals with an MMSE score < 18; (2) individuals with 1-6 years of education with an MMSE score < 21; and (3) individuals with > 6 years of education with an MMSE score < 25 [20].

Vitamin D levels

25(OH)D is the most reliable surrogate measure for vitamin D levels in the human body [21]. Biomarker study participant blood samples were collected in vacuum tubes containing heparin by trained medical professionals, after which they were centrifuged at 2500 rpm for 10 min at 20℃. Plasma 25(OH)D levels were then measured via ELISA (Immunodiagnostic Systems Limited, Bolton, UK), with participants being separated into quartiles based on these 25(OH)D concentrations (<27.1, 27.1-37.9, 37.9-52.4, and ≥52.4 nmol/L).

Covariates

Covariates with the potential to influence study outcomes that were assessed in this analysis included baseline age, sex, marital status (married vs. other [never married, divorced, or widowed]), years of education (0 vs. 1 or more years), residence (urban vs. rural), co-residence (with family members vs. living alone or in an institution), economic independence (having own labor income/a retirement wage vs. other), current drinker status (yes or no), current smoker status (yes or no), current regular exercise (yes or no), body mass index (BMI), season during which blood was collected, chronic comorbidities, albumin levels, triglyceride levels, hemoglobin levels, high-density lipoprotein (HDL) levels, and high-sensitivity C-reactive protein (hs-CRP) levels. BMI was measured by dividing participant weight (kg) by height (m) squared, with patients with a BMI <18.5 kg/m², 18.5-24 kg/m², 24-28 kg/m², and ≥28 kg/m² respectively being respectively considered to be underweight, normal weight, overweight, and obese. Chronic comorbidities considered in this study included physician-diagnosed diabetes, stroke, hypertension, cerebrovascular disease, cancer, asthma, pneumonia, emphysema, tuberculosis, and bronchitis, with participants being separated into those with 0, 1, 2, or 3+ chronic diseases. eGFR was calculated with the improved 4-variable Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (adjustment factor 1.1) [22].The central clinical laboratory of Capital Medical University measured all blood biomarker levels.

Statistical analysis

Continuous variables in this study exhibited skewed distributions. Baseline participant characteristics were reported as medians with interquartile ranges (IQRs) or percentages. Categorical and baseline continuous variables were respectively compared using chi-square and Kruskal-Wallis tests.

The effects of vitamin D levels on cognitive status were assessed through bivariate logistic regression analyses. Relationships between all-cause-mortality and vitamin D levels and cognitive function at baseline were assessed through the use of Kaplan-Meier survival curves and the log-rank test. Cox proportional hazard models were used to estimate all-cause mortality hazard ratios (HRs) and 95% confidence intervals (CIs) associated with vitamin D levels of cognitive status, while the association between cognitive function and all-cause mortality stratified according to plasma 25(OH)D quartiles were evaluated using multivariate proportional hazards regression models, with normal cognition and the 25(OH)D quartile 4 serving as a reference for the purposes of these analyses. Schoenfeld residuals were additionally utilized to test the proportionality assumption, with the result being met (P > 0.05 for all-cause mortality). Candidate variables with a P value <0.05 on univariate analysis for cognitive function were included as covariates in adjusted models. We set up the unadjusted model, age and sex adjusted model, and the multivariable-adjusted model for the outcome. Multiplicative interactions were examined by incorporating a cross-product term corresponding to cognitive function and plasma 25(OH)D. Ordinal values were used to examine tests for trends across vitamin D quartiles under different models. Mortality rates were estimated for different vitamin D levels (quartiles) and levels of cognitive function (cognitive impairment vs. normal cognition).

All analyses were performed using R v 4.1.3 (R Foundation for Statistical Computing), with a two-tailed P < 0.05 as the significance threshold.

Cross-sectional analysis findings

Of the 2,154 individuals enrolled in the present study cohort, 414 (19.2%) exhibited baseline cognitive impairment. The characteristics of participants stratified according to cognitive function status are compiled in Table 1. Relative to participants exhibiting normal cognitive function, those suffering from cognitive impairment had a higher chance of being female, older, not married (unmarried, divorced, or widowed), less educated, non-drinkers, non-smokers, and economically dependent. These cognitively impaired participants were also more likely to exhibit lower albumin, eGFR, hemoglobin, and 25(OH)D levels, as well as elevated levels of hs-CRP.

Table 1 Baseline participant characteristics grouped based on cognitive function

Characteristics	Overall (N = 2154)	Normal cognition (N = 1740)	Cognitive impairment (N = 414)	P value^a
Sociodemographic characteristics
Age, median (IQR), years	85 (76.0, 95.0)	82 (74.0, 91.0)	99 (91.0,101.0)	<0.001
Female, no. (%)	1165 (54.1)	852 (49.0)	313 (75.6)	<0.001
Married, no. (%)	876 (40.7)	814 (46.8)	62 (15.0)	<0.001
Rural, no. (%)	1734 (80.5)	1398 (80.3)	336 (81.2)	0.707
Education (≥ 1 year), no. (%)	768 (35.7)	719 (41.3)	49 (11.8)	<0.001
With household member(s), no. (%)	1620 (75.2)	1314 (75.5)	306 (73.9)	0.497
Economic independence, no. (%)	493 (22.9)	472 (27.1)	21 (5.1)	<0.001
Health characteristics, no. (%)
Smoking status				<0.001
Current	345 (16.0)	322(18.5)	23 (5.6)
Never or former	1809 (84.0)	1418(81.5)	391 (94.4)
Drinking status				<0.001
Current	321 (14.9)	292 (16.8)	29 (7.0)
Never or former	1833 (85.1)	1448 (83.2)	385 (93.0)
Regular exercise	329 (15.3)	300 (17.2)	29 (7.0)	<0.001
BMI (kg/m²)				0.813
<18.5	1233 (57.2)	986 (56.7)	247 (59.7)
18.5–24	442 (20.5)	320 (18.4)	122 (29.5)
24–28	376 (17.5)	341 (19.6)	35 (8.5)
≥28	103 (4.8)	93 (5.3)	10 (2.4)
Chronic disease
None	1192 (55.3)	968 (55.6)	224 (54.1)	0.813
One chronic disease	675 (31.3)	538 (30.9)	137 (33.1)
Two chronic diseases	215 (10.0)	174 (10.0)	41 (9.9)
Three or more chronic diseases	72 (3.3)	60 (3.5)	12 (2.9)
Season of blood draw				<0.001
Spring	882 (41.0)	659 (37.9)	223 (53.9)
Summer	1170 (54.3)	987 (56.7)	183 (44.2)
Autumn	102 (4.7)	94 (5.4)	8 (1.9)
Biomarkers, median (IQR)
25(OH) D (nmol/L)	37.90 (27.14, 52.39)	40.13 (29.00, 54.34)	28.68 (20.80, 42.43)	<0.001
Albumin (g/L)	41.70 (38.60, 44.20)	42.10 (39.10, 44.60)	39.50 (36.88, 42.30)	<0.001
hs-CRP (mg/L)	1.00 (0.44, 2.42)	0.97 (0.42, 2.35)	1.17 (0.54, 3.08)	0.003
GFR (ml/min per 1.73 m²)	76.12 (61.02, 88.81)	78.15 (62.73, 90.85)	68.10 (53.80, 80.48)	<0.001
HDL cholesterol (mmol/L)	1.32 (1.09, 1.58)	1.31 (1.09, 1.58)	1.36 (1.09, 1.58)	0.363
Triglyceride (mmol/L)	0.94 (0.69, 1.30)	0.94 (0.68, 1.32)	0.91 (0.72, 1.18)	0.392
Hemoglobin	125.00 (114.00, 139.00)	127.00 (114.00 141.00)	121.00 (110.00, 132.00)	<0.001

BMI body mass index, 25(OH)D 25-Hydroxyvitamin D, hs-CRP high-sensitive C-reactive protein, GFR glomerular filtration rate, HDL high-density lipoprotein

Notes: ^aP-values for continuous and categorical variables were respectively calculated using Kruskal-Wallis and chi-square tests

Individuals in the lowest plasma 25(OH)D quartile (quartile 1) were more likely to exhibit cognitive impairment (odds ratio [OR] 1.61, 95%CI 1.08 to 2.39) as compared to participants with the highest plasma 25(OH)D levels (quartile 4) (Table 2).

Table 2 The relationship between plasma vitamin D levels and cognitive impairment

25(OH)D (nmol/L)	Unadjusted Model		Model 1		Model 2
25(OH)D (nmol/L)	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
Quartile 1 (<27.1)	4.37 (3.15, 6.07)	<0.001	2.31 (1.50, 3.34)	<0.001	1.61 (1.08, 2.39)	0.018
Quartile 2 (27.1-37.9)	1.88 (1.33, 2.68)	<0.001	1.21 (0.82, 1.79)	0.331	1.00 (0.66, 1.50)	0.99
Quartile 3 (37.9-52.4)	1.36 (0.94, 1.97)	0.100	1.21 (0.81, 1.81)	0.356	1.08 (0.72, 1.64)	0.705
Quartile 4 (≥52.4)	Reference		Reference		Reference
P for trend	<0.001		<0.001		0.014

25(OH) D 25-Hydroxyvitamin D, OR odds ratio, CI confidence interval

Notes: Model 1: adjusted for age and sex; Model 2: additionally adjusted for season of blood draw, economic status, marital status, drinking status, smoking status, level of education, regularity of exercise, eGFR, hs-CRP, hemoglobin, and albumin levels

Longitudinal result analyses

In total, this analysis incorporated 8,222.5 person-years of follow-up data, with the longest follow-up interval being 6.5 years and a median follow-up of 3.5 years. Cognitively impaired individuals were found to be at an elevated risk of all-cause mortality relative to non-cognitively impaired individuals (HR 1.75, 95% CI: 1.49 to 2.06), while vitamin D levels exhibited an inverse dose-response relationship with mortality (P < 0.001) (Table 3).

Table 3 Risk of all-cause mortality according to cognition function and vitamin D levels

Variable	Unadjusted Model		Model 1		Model 2
Variable	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Cognitive function^a
Cognitive impairment	4.06 (3.52, 4.69)	<0.001	1.89 (1.61, 2.21)	<0.001	1.75 (1.49, 2.06)	<0.001
Normal cognition	Reference		Reference		Reference
25(OH)D (nmol/L)^b
Quartile 1 (<27.1)	2.96 (2.43, 3.62)	<0.001	2.14 (1.74, 2.63)	<0.001	2.03 (1.63, 2.53)	<0.001
Quartile 2 (27.1-37.9)	1.79 (1.45, 2.21)	<0.001	1.51(1.22, 1.87)	<0.001	1.48 (1.19, 1.85)	<0.001
Quartile 3 (37.9-52.4)	1.25 (1.00, 1.56)	0.049	1.22 (0.98, 1.53)	0.08	1.18 (0.94, 1.48)	0.158
Quartile 4 (≥52.4)	Reference		Reference		Reference
P for trend	<0.001		<0.001		<0.001

25(OH) D 25-Hydroxyvitamin D, HR hazards ratios, CI confidence interval

Notes: Model 1: adjusted for age and sex; Model 2:^aadditionally adjusted for season of blood draw, economic status, marital status, drinking status, smoking status, level of education, regularity of exercise, 25(OH) D, eGFR, hs-CRP, hemoglobin, and albumin levels; ^badditionally adjusted for season of blood draw, economic status, marital status, drinking status, smoking status, level of education, regularity of exercise, cognitive function, eGFR, hs-CRP, hemoglobin, and albumin levels

The estimated odds of survival over time as a function of baseline vitamin D levels and cognitive function are shown in Figure 1. Respective median survival durations for individuals exhibiting cognitive impairment and individuals in 25(OH)D quartile 1 were 34.5 and 46 months, respectively. Survival curves were generated for eight different groups of study participants separated based upon baseline vitamin D levels and cognitive function (Figure 2). These analyses revealed that the median survival time of cognitively impaired individuals was positively correlated with baseline vitamin D levels, with respective median survival durations of 30, 34, 41, and 52 months for individuals in 25(OH)D quartiles 1, 2, 3, and 4.

The combined impact of plasma 25(OH)D levels and cognitive status on all-cause mortality was next assessed, with individuals with normal cognition in plasma 25(OH)D quartile 4 serving as the reference population (Figure 3). A negative dose-response relationship was observed between 25(OH)D levels and the odds of mortality among cognitively impaired individuals (quartile 1 of 25(OH)D: HR 3.57, 95% CI: 2.68 to 4.75; quartile 2: HR 2.73, 95% CI: 1.98 to 3.76; quartile 3: HR 2.21, 95% CI: 1.55 to 3.16; quartile 4: HR 2.05, 95% CI: 1.36 to 3.09). Moreover, the risk of mortality for individuals with normal cognition in plasma 25(OH)D quartiles 1 or 2 was significantly elevated as compared to that for individuals in plasma 25(OH)D quartile 4 (quartile 1: HR 2.18, 95% CI: 1.68 to 2.84; quartile 2: HR 1.53, 95% CI: 1.18 to 1.97). When assessing the risk of all-cause mortality, a significant interaction was detected between vitamin D levels and cognitive function (P for interaction < 0.001) (Figure 4).

Relative to cognitively normal individuals, cognitively impaired study participants exhibited significantly increased rates of all-cause mortality per 100 person-years (21.4% and 59.93%, respectively) over the course of follow-up. Similarly, vitamin D levels exhibited a negative dose-response relationship with all-cause mortality (Table 4). For individuals with normal cognition at baseline, all-cause mortality rates (per 100 person-years) were 31.7%, 23.6%, 17.9%, and 16.5% for individuals in 25(OH)D quartiles 1, 2, 3, and 4, respectively, whereas for cognitively independent individuals these respective rates were 66.0%, 65.0%, 53.1%, and 43.2%.

Table 4 Participant all-cause mortality rates as a function of vitamin D level and cognitive status

25(OH)D (nmol/L)	All participants^a (N = 2,154)	Normal cognition at baseline^b (N = 1,740)	Cognitive impairment at baseline^c (N = 414)
25(OH)D (nmol/L)	Mortality, no. (per 100 person-year, %)	Mortality, no. (per 100 person-year, %)	Mortality, no. (per 100 person-year, %)
Quartile 1 (<27.1)	304 (40.5)	158 (31.7)	146 (66.0)
Quartile 2 (27.1-37.9)	225 (29.2)	150 (23.6)	75 (65.0)
Quartile 3 (37.9-52.4)	168 (21.5)	119 (17.9)	49 (53.1)
Quartile 4 (≥52.4)	142 (18.5)	110 (16.5)	32 (43.2)

25(OH) D 25-Hydroxyvitamin D

Notes: ^aSample sizes: quartiles 1-4: 539, 537, 540 and 538, respectively. ^bSample sizes: quartiles 1-4: 355, 439, 465 and 481, respectively. ^cSample sizes: quartiles 1-4: 184, 98, 75 and 57, respectively

In the present prospective analysis of 2,154 Chinese adults 65 + years old, both cognitive impairment and lower vitamin D concentrations were associated with elevated risk of all-cause mortality, and the combination of these two factors had a cumulative impact on such risk. A significant interaction was observed between 25(OH)D concentrations and cognitive status with respect to mortality risk. Moreover, a significant inverse dose-response relationship was detected between baseline cognitive status and plasma 25(OH)D levels. This study was also the first to detect the additive impact of vitamin D concentrations and cognitive function on all-cause mortality.

The link between cognitive impairment and a higher risk of death detected in this study has also been reported previously [23–25]. For example, one study of 77,541 individuals 65 years of age or older found that relative to normal cognition, mild, moderate, and severe cognitive impairment were significantly associated with mortality risk, with respective HRs of 1.67 (95% CI: 1.43–1.94), 2.26 (95% CI: 1.90–2.70), and 2.68 (95% CI: 2.25–3.19) [23]. A separate prospective large-scale study conducted in China with a 6-year follow-up found cognitive impairment, as measured using education level-adjusted MMSE scores, was closely related to all-cause mortality risk among adults 65 years of age or older [25]. The results of the present study are also consistent with prior evidence linking lower vitamin D concentrations to a higher risk of death [7, 15, 16]. Studies exploring the prognostic implications of the combined effects of vitamin D levels and cognitive impairment, however, have been limited to date.

The results of this study expand upon prior evidence pertaining to the impact of vitamin D levels as a risk factor related to cognitive impairment [26, 27], providing new insight regarding how these levels interact with cognitive status to modulate all-cause mortality risk. Notably, cognitively impaired study participants with lower plasma 25(OH)D levels exhibited a significantly higher risk of death, suggesting that monitoring vitamin D concentrations may represent an effective approach to detecting risk in cognitively impaired older adults. The mechanistic basis for this relationship, however, remains to be established. One potential explanation for these results may be that vitamin D deficiencies may contribute to the onset of cognitive impairment. In line with previous reports [28–30], the present cross-sectional analyses demonstrated that individuals exhibiting lower circulating 25(OH)D levels were at a higher risk of cognitive impairment. In both human and animal studies, vitamin D has been shown to protect against inflammation-related neurodegeneration [31], to reduce amyloid-β production while increasing amyloid-β clearance[32], and to prevent neurodegeneration [33]. In one interventional study, vitamin D supplementation for 6 months resulted in improved mental status and plasma Aβ1–40 concentrations in MCI patients [34]. Vitamin D deficiency may also contribute to cardiovascular disease and atherosclerosis development by inducing the proliferation of vascular smooth muscle cells, promoting inflammatory activity, and driving the dysfunctional activity of endothelial cells and epicardial fat [35]. There is also evidence that vitamin D can suppress the formation of foam cells and reverse atherosclerotic development [36]. The risk of cancer can also increase in the absence of sufficient vitamin D levels, with higher rates of colorectal and breast cancer development having been reported in vitamin D deficient individuals [37, 38]. Vitamin D can suppress tumor development and slow oncogenic progression by inhibiting invasivity, proliferation, angiogenesis, and inflammation while simultaneously promoting apoptotic cell death [39]. Vitamin D deficiency has also been shown to contribute to the incidence of secondary hyperparathyroidism, resulting in elevated levels of parathyroid hormone (PTH) that have been tied to impaired physiological functionality and frailty [40]. Given that cardiovascular disease, frailty, cancer, and cognitive impairment are all risk factors for mortality, vitamin D deficiency may contribute to higher rates of death by adversely affecting a range of organs.

These results indicate that efforts to maintain appropriate levels of circulating 25(OH)D may aid in the prevention of premature mortality among older adults, particularly in those suffering from cognitive impairment. This is particularly noteworthy given that vitamin D levels can be safely and economically modified through supplementation. If the maintenance of appropriate levels of vitamin D can reduce the odds of cognitive impairment-related death, then such supplementation may represent a valuable means of protecting against mortality. Further randomized controlled trials, however, will be necessary to test the efficacy of this interventional strategy.

A key strength of this study is that the data are derived from a representative population of older Chinese adults, allowing for the longitudinal analysis of the interplay between vitamin D levels, cognitive impairment, and all-cause mortality over a 6-year period. However, there are multiple limitations to this analysis that should be taken into consideration. For one, only baseline vitamin D levels and cognitive status were measured in study participants, and changes in these parameters over the course of the study were thus not assessed. Second, the MMSE was used to gauge cognitive impairment without any corresponding clinical diagnosis, precluding the potential of determining whether or not older adults are suffering from dementia. Lastly, the results of these analyses may have been impacted by other covariates that were not measured or considered.

In summary, the results of this analysis suggest that lower levels of vitamin D are related to the incidence of cognitive impairment in an older Chinese adult population. Moreover, cognitive impairment and low vitamin D levels exhibited an additive interactive effect on all-cause mortality in this population. As such, efforts to screen for vitamin D deficiency and cognitive status in combination with appropriate pharmacological or nutritional interventions aimed at improving plasma 25(OH)D concentrations may help to decrease the incidence of premature mortality among older adults. However, further mechanistic analyses will be essential to fully clarify how vitamin D can prevent mortality in cognitively impaired older adults.

25(OH)D, 25-Hydroxyvitamin D; OR, odds ratio; CI, confidence interval; CLHLS, Chinese Longitudinal Healthy Longevity Survey; IQR, interquartile range; BMI, body mass index; hs-CRP, high-sensitive C-reactive protein; GFR glomerular filtration rate, HDL high-density lipoprotein.

Ethics approval and consent to participate

This study was performed according to the Helsinki Declaration. All participants or their proxies gave informed consent to participate in the study and consented to the use of their data. The Biomedical Ethics Committee of Peking University approved this study (IRB00001052-13074).

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from Peking University but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Peking University.

Competing interests

The authors declare that they have no conflict of interest.

Funding

This study was supported by grants from the Chinese National Science & Technology Pillar Program (2020YFC2005600), Sichuan Science and Technology Program (2019YFS0277), 1·3·5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University(19HXFH012), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20191003, Z2018B13).

Author’s contributions

JY and MD conceptualized and designed the study. JY obtained funding. MD, QS, XW, TL, RL, JT and SX collected and interpreted the data. MD and QS analyzed data, prepared and reviewed figures. MD wrote the original draft. JY provided critical revisions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We thank the CLHLS who collected and reported data and made the data publicly available to researchers. The funder had no role in study design, data collection, data analysis, or preparation of this manuscript. All authors have no conflict of interest to declare.

Authors’ information

¹Department of geriatrics, Jiujiang First People's Hospital, Jiujiang 332000, Jiangxi, China. ²Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.³Department of Cardiology, Jiujiang First People's Hospital, Jiujiang 332000, Jiangxi, China.

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The Impact of Vitamin D and Cognitive Function on All-Cause Mortality Among Older Chinese Adults: A Population-based Longitudinal Study

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