Vitamin D Supplement Intake is Associated with Better Cognition in Persons with Sleep Disturbance and Mild Cognitive Impairment

Abstract

Introduction:

Sleep disturbances affect nearly half of individuals with mild cognitive impairment (MCI), a population at elevated risk for progression to Alzheimer’s disease (AD). Vitamin D’s role in cognitive outcomes, particularly among individuals with sleep disturbance, remains unclear. This study explored associations between cognitive function and vitamin D supplement intake in individuals with MCI and sleep disturbance-a high-risk group that may be more vulnerable to progression toward Alzheimer’s disease.

Methods:

This cross-sectional study included 54 participants with diagnosed or suspected mild cognitive impairment (MCI) and disturbed sleep (as determined by validated sleep questionnaires). We administered the MoCA (Montreal Cognitive Assessment) to assess cognition. Disturbed sleep was defined using the Pittsburgh Sleep Quality Index (PSQI ≥ 5) or the Epworth Sleepiness Scale (ESS ≥ 10). Vitamin D supplement intake was assessed by self-reported questionnaire. A multiple linear regression model was utilized to examine the association between vitamin D supplement intake and cognitive impairment (MoCA score), controlling for covariates of age, sex, body mass index (BMI), vitamin D type, and education.

Results:

Participants had a mean age of 67.2±8.9, a mean BMI of 29.5±7.2 kg/m², and 46% were male. Participants who took a daily dosage of 5000+ IU of vitamin D showed a marginally significant association with total MoCA score (adjusted mean (SE) = 3.78 (1.77); p = 0.039) in comparison to individuals who did not take daily vitamin D. Having a college degree was significantly associated with a higher total MoCA score (adjusted mean (SE) = 3.14 (1.38); p = 0.031). Individuals who were overweight also demonstrated higher total MoCA scores (adjusted mean (SE) = 3.59 (1.36); p = 0.013). No significant differences were found between individuals who regularly took vitamin D3 versus D2. Lower doses of Vitamin D did not significantly impact total MoCA score.

Conclusion:

To our knowledge, this is the first study to evaluate the relationship between vitamin D supplementation and overall global cognition in individuals with both sleep disturbance and MCI. Our findings suggest that taking higher doses of daily vitamin D supplementation is associated with better overall cognitive performance in this population.

Introduction:

Mild Cognitive Impairment (MCI) represents a transitional state between normal aging and early dementia [1]. Among individuals with MCI, sleep disturbance is highly prevalent, impacting approximately 36% based on subjective measures and 46% based on objective measures [2]. Approximately 20% of older adults are affected by MCI [3]. Among individuals with MCI, an estimated 27% progress to Alzheimer’s Disease (AD) annually [4]. Subsequently, this state may represent an important window for early intervention, as MCI has been identified as a critical stage for clinical management [5]. Micronutrient supplementation has been proposed as a pragmatic, minimally invasive approach to support overall cognitive function, and has been examined in the context of sleep disorders [6] and, separately, in populations with MCI [7] or AD [8, 9]. However, these areas of research have largely been explored independently. Vitamin D supplementation, in particular, has been found to improve cognitive function in older adults with MCI [10]. However, a systematic review on the effects of Vitamin D supplementation on cognitive function noted that findings remain mixed [11].

Sleep disturbances are associated with poorer cognitive outcomes [12, 13]. Evidence suggests a bi-directional relationship between MCI and sleep disturbances [14], and several mechanisms have been proposed to explain this link, including neuroinflammation [15] and amyloid beta (Aβ) accumulation [16]. Emerging evidence suggests vitamin D supplementation may be associated with improved sleep quality [17], although findings across the broader literature are mixed.

Given established associations between sleep quality, cognitive function, and vitamin D status, further investigation into the role of vitamin D in cognitive outcomes among individuals with sleep disturbance is warranted. Although vitamin D deficiency has been associated with increased risk of cognitive decline [18] and sleep disorders [19], findings regarding the effects of Vitamin D supplementation and optimal dosing strategies remain uncertain. To our knowledge, no study has specifically assessed the effect of Vitamin D supplementation in a population with both MCI and sleep disturbance. Taken together, these associations highlight the need for further investigation into how Vitamin D relates to cognition in these at-risk populations.

The study examined the association between daily Vitamin D intake and cognition in persons with both MCI and sleep disturbance. We hypothesized that higher doses of daily Vitamin D supplementation would be associated with better cognitive performance in this population.

2. Materials and Methods

2.1. Study Sample and Design

This exploratory cross-sectional study was composed of individuals with MCI and sleep disturbances. Eligible participants were enrolled after written informed consent or e-consent was obtained by study coordinator and research personnel. When appropriate, a study partner or legally authorized representative (LAR) assisted with questionnaires and were not required to be on site during clinic visits. Trained research staff obtained current medical history, medications, and dietary supplement use at baseline. Standardized questionnaires and tests were then administered to participants to assess sleep and cognition. The study protocol was approved by the Emory Institutional Review Board, and all participants provided informed consent.

2.2. Inclusion and Exclusion Criteria

Participants were eligible for inclusion if they were 50 years of age or older, clinically diagnosed with mild cognitive impairment (MCI) or suspected to have MCI based on a Montreal Cognitive Assessment (MoCA) Test for Dementia score range of 18 through 25, and had evidence of sleep disturbance defined as either a Pittsburgh Sleep Quality Index (PSQI) total score of 5 or greater, or an Epworth Sleepiness Scale (ESS) score of 10 or greater.

Participants were excluded if they: 1) had no telephone access; 2) were currently taking any medication known to affect rapid eye movement (REM) sleep or sleep architecture in general; 3) reported use of choline supplements; 4) had a history of epilepsy or head trauma resulting in unconsciousness within the past two years; 5) had a history of alcohol dependence or drug abuse; or 6) were night shift workers or in situations where they regularly experienced jet lag or had irregular work schedules. Participant demographics are summarized in Table 1.

Table 1:

Summary of participant demographics

Characteristic	Total N=54
Age (years)	67.2 (8.9)
Sex (male)	25 (46.3%)
Body Mass Index (kg m−2)	29.5 (7.2)
Healthy Weight (18.5 – 25)	16 (29.6%)
Overweight (25 – 30)	15 (27.8%)
Obese (30+)	23 (42.6%)
Vitamin D Dosage (<1000 IU)	4 (7.4%)
Vitamin D Dosage (1000 – 1999 IU)	5 (9.3%)
Vitamin D Dosage (2000 – 4999 IU)	6 (11.1%)
Vitamin D Dosage (5000+ IU)	12 (22.2%)
Vitamin D2 Use (Yes)*	8 (14.8%)
Vitamin D3 Use (Yes)*	27 (50.0%)
Education (≤High School)	12 (22.6%)
Education (College)	21 (39.6%)
Education (>College)	20 (37.7%)
Total MoCA score	24.1 (3.6)
ESS	9.38 (4.8)
Global PSQI	10.2 (3.9)

^*Percentage of participants reporting intake vs non-intake

Data are presented as mean (SD); Categorical variables are presented as n (%)

2.3. Sleep Measures

The Pittsburgh Sleep Quality Index (PSQI) is a self-administered questionnaire that assesses multiple domains of sleep [20]. A global PSQI score of 5 or greater distinguished participants with poor sleep quality.

The Epworth Sleepiness Scale (ESS), a widely used standardized self-report instrument [21], was used to measure sleepiness. This questionnaire asks subjects to rate their chance of dozing during 8 common situations. The responses are based on a Likert-type scale ranging from 0 to 3, with 0 indicating no chance of dozing and 3 indicating a high chance of dozing. The sum of these responses determines the total ESS score, with higher scores indicating greater sleepiness [21]. Subjects were categorized as having excessive daytime sleepiness (EDS) if they had an ESS score ≥10, consistent with prior studies [22, 23].

The PSQI and ESS were selected to screen for either poor sleep quality or presence of excessive daytime sleepiness, respectively-representing two distinct yet complementary dimensions of sleep disturbance [20, 21]. Together, this approach allows for a broader characterization of sleep disturbance by ensuring inclusion of sleep impairment across multiple domains.

2.4. Cognitive Measures

The Montreal Cognitive Assessment (MoCA) is a validated screening tool that assesses global cognitive function. Normal cognitive performance is reported at a cutoff of 26 and above, and MCI is defined within the range of 18 – 25 [24].

2.5. Vitamin Intake Measures

Vitamin D intake was self-reported by participants where they answered questions on daily dosages and whether they took Vitamin D2 vs D3. Vitamin D intake was categorized using ranges consistent with those defined in the Harvard Semi-Quantitative Food Frequency Questionnaire (<1000 IU, 1000 – 1999 IU, 2000 – 4999 IU, 5000+ IU) [25].

2.6. Data analyses

Descriptive statistics were calculated for demographic and clinical variables. Continuous variables were presented as mean (SD) and categorical variables as frequency and percentage. Vitamin D dosage was categorized using standardized FFQ ranges [25], with “None” serving as the reference group. Vitamin D type was categorized as a binary variable with “No Intake” as the reference group. To examine the relationship between daily Vitamin D dosage and global MoCA scores, we applied a multivariable linear regression model in which global MoCA score was treated as the dependent variable and regressed against the categorical daily Vitamin D intake, adjusting for the following covariates: age, sex, BMI, vitamin D type, and education. The model was fit using a generalized linear model with Gaussian distribution and identity link. Linear regression assumptions were evaluated prior to interpretation using residual diagnostics, Q–Q plots, Shapiro–Wilk testing, variance inflation factors, and influence statistics (leverage and Cook’s distance). Daily Vitamin D intake of 5000 IU+ emerged as most significantly associated with global MoCA score. Given the evidence that BMI may influence responses to the effects of different vitamin D supplement types [26], we assessed for an interaction between BMI and Vitamin D type. We collapsed BMI category to a binary variable (Healthy BMI 18.5 – 25, Overweight / Obese BMI 25 +), and a secondary multivariable linear regression model with the addition of Vitamin D type * BMI (binary) as an interaction variable. All statistical analyses were performed using R (version 4.5.1, R Foundation for Statistical Computing, Vienna, Austria). Given the exploratory nature of this study, a two-sided p-value of less than 0.05 was considered to be statistically significant.

3. Results

Summary statistics of patient demographics are presented in Table 1. The mean age was 67.2 (8.9), the mean BMI was 29.5±7.2 kg/m², 46.0% were male, and 22.6% reported lower than a college-level education. 98.1% were poor sleepers based on a PSQI ≥ 5 and 42.6% were sleepy based on an Epworth ≥ 10. 40.7% met both criteria. In multivariate analyses, there was a significant correlation between 5000 IU+ daily Vitamin D intake and global MoCA score (Table 2). Participants with a college level education have significantly higher global MoCA scores, and participants classified as overweight (via BMI) also displayed higher global MoCA scores (Table 2). Given the relatively small number of participants in the 5000+ IU category (n = 12) and borderline statistical significance of this finding (p = 0.039), these findings should be interpreted with caution and considered preliminary. We found no significant differences in Vitamin D type or interaction effects between Vitamin D type and BMI (binary) on cognition (Supplemental Table 1).

Table 2:

Results of the multiple regression analysis of total MoCA score as a function of Vitamin D Dosage (see below) with adjusted covariates including age, sex, BMI (categorical), Vitamin D type, and education.

Dependent Variable	Estimate	SE	P-value
Daily Dosage of Vitamin D (<1000 IU)	2.07	2.21	0.354
Daily Dosage of Vitamin D (1000–1999 IU)	0.574	2.12	0.787
Daily Dosage of Vitamin D (2000–4999 IU)	0.726	1.99	0.717
Daily Dosage of Vitamin D (5000+ IU)	3.78	1.77	0.0387*
Sex (Male vs. Female)	−1.38	1.24	0.289
Age at Enrollment	0.0313	0.0707	0.650
BMI Category (Overweight vs. Healthy)	3.59	1.36	0.0134*
BMI Category (Obesity vs. Healthy)	2.05	1.36	0.148
Vitamin D2 Use (Yes vs. No)	1.69	1.47	0.269
Vitamin D3 Use (Yes vs. No)	−2.70	1.50	0.0834
Education (College vs. ≤High School)	3.14	1.38	0.0309*
Education (>College vs. ≤High School)	1.82	1.55	0.253

Factors with significant correlation with total MoCA score are marked using asterisk*. Estimates (β coefficients) represent adjusted mean differences in MoCA score from multivariable linear regression. Reference categories: Vitamin D dosage = None; Sex = Female; BMI = Healthy weight; Vitamin D2/D3 use = No; Education ≤ High School.

4. Discussion

Our analysis on daily Vitamin D intake in a sample of individuals with both MCI and sleep disturbance demonstrated that high dose Vitamin D supplementation is associated with better cognition. To our knowledge, this is the first study to examine the effect of daily Vitamin D dosage ranges on a population with co-occurring MCI and sleep disturbance. These findings are exploratory, necessitating confirmation in follow-up studies with larger sample sizes. This study provides insight into the relationship between vitamin D supplementation and cognition in this high-risk group. Importantly, we examine Vitamin D dose categories and their effect on cognition.

Vitamin D supplementation trials have shown improved cognition in individuals with MCI and sleep disturbances separately, although dosage regimens and outcomes differ considerably across studies [11] which limits direct comparisons. One study in 82 healthy adults found that the High Dose Vitamin D Supplementation Group (4000 IU) performed better on nonverbal (visual) memory tasks than the Low Dose Group (400 IU) [27]. The observed effects were modest and require replication in larger studies. Considering that the MoCA assesses multiple cognitive domains, including executive and visuospatial abilities [24] and prior studies have examined visuospatial cognitive performance in the context of Vitamin D supplementation [27], these findings provide contextual support for interpreting our results.

Vitamin D3 is commonly used in Vitamin D supplementation studies examining cognition [10, 28] or sleep [29]. Vitamin D3, cholecalciferol, has been shown to be more effective than D2 (ergocalciferol) in increasing total 25(OH)D levels [30]. This effect may be related to the shorter plasma half-life of ergocalciferol compared to cholecalciferol, which has been shown to vary with vitamin D binding protein (DBP) concentration and genotype [31]. A randomized controlled trial of Vitamin D in older adults (n = 436) found no significant effects of treatment, whether from D2 (via enhanced D2 in a mushroom matrix) or D3, on cognitive function when compared to placebo or between treatment groups [32]. We also observed no significant differences in the association between taking Vitamin D2 and Vitamin D3 supplementation on global MoCA after adjustment for covariates. This could suggest that in persons with both MCI and sleep disturbance, Vitamin D dosage potentially has a greater effect than Vitamin D type.

Beyond Vitamin D intake, BMI category was associated with global MoCA score in adjusted analyses. Specifically, overweight status was associated with higher MoCA scores in comparison to healthy weight, while the obesity category was not statistically significant in comparison to healthy weight. This pattern appears broadly consistent with prior studies suggesting an ‘obesity paradox,’ in which higher BMI has been associated with a lower risk of cognitive impairment in certain populations, although findings across studies are mixed and context-dependent [33–35]. BMI may also not be the best proxy for excess adiposity in older adults [36]. The “obesity paradox”, defined as a protective association between BMI and certain clinical outcomes, remains controversial due to mixed results and the influence of multiple confounding factors [37]. Our findings add to this discussion by finding an association between overweight status and cognition. While no statistically significant association was observed between obesity status and MoCA, prior studies suggest that the relationship between BMI and cognitive performance may vary across specific domains. One study observed that obesity may be associated with cognitive flexibility as assessed by the Trail Making Test (TMT-B) [36]. This may reflect limited statistical power within BMI categories, as unmeasured heterogeneity in disease risk profiles may not be captured fully by BMI alone. Moreover, a study by Chen and colleagues have reported associations between higher BMI and poorer cognitive performance, including executive function in adults aged 60 and older [38]. A prospective study of 7,029 adults found that lower baseline memory scores were associated with a faster annual decline in BMI over the subsequent decade, suggesting a potential reverse causation explanation for the “obesity paradox” [39]. Future studies should examine the longitudinal relationship between adiposity measures beyond BMI and cognitive outcomes in older adults to clarify this association.

While Vitamin D3 was associated with a greater increase in serum 25(OH)D levels compared to Vitamin D2; this difference was no longer statistically significant among individuals with a BMI >25kg/m2 [26]. One explanation may be the fact that Vitamin D, a fat-soluble vitamin, is stored in adipose tissue [40, 41]. Evidence suggests that a higher BMI is associated with a reduced response in circulating 25(OH)D levels in response to vitamin D supplementation [42]. As reported in a recent meta-analysis and systematic review, BMI appears to modify the response to vitamin D supplementation, with differences between vitamin D2 and D3 attenuated in individuals with higher BMI [26]. While we did not find a significant interaction effect between BMI and Vitamin D type on cognition, daily Vitamin D supplementation (5000 IU+) was associated with overall better cognitive performance. However, it is important to note that evidence regarding the cognitive benefits of Vitamin D supplementation remain mixed [11].

Similar to BMI, participants with college level education appeared to have higher MoCA scores in comparison to those with ≤ high school education, whereas graduate level education was not statistically significantly associated with MoCA scores. Directionally, these results are consistent with prior findings showing that higher years of educational attainment is associated with better MoCA performance [43, 44]. Sex and age were also not significantly associated with MoCA score. While not statistically significant, the direction of the sex-specific estimate is consistent with reports of lower average MoCA scores in men compared to women [45, 46]. The null finding may be due to the restricted age range of over 50 with limited variability within our sample.

We chose to explore Vitamin D supplementation in our study population based on our previous publication which discussed neuroinflammation as a mediating link between sleep disturbances and MCI [15]. A review examining the role of Vitamin D in inflammatory diseases suggests that Vitamin D plays a role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and attenuating pro-inflammatory immune responses [47]. Poor sleep quality has been independently associated with elevated inflammatory activity [48]. Neuroinflammation may induce neurodegenerative processes [49]. A prior study found that neurocognitive performance was negatively associated with IL-18, a pro-inflammatory cytokine, and positively associated with subjective sleep quality [50]. Additionally, poor subjective sleep quality mediated the association between higher IL-18 and poorer neurocognitive performance when IL-12 levels were elevated [50].

Sleep disturbance in individuals with MCI has been associated with progression to Alzheimer’s and adverse health outcomes [51]. While prior work has examined the interaction between Vitamin D3, sleep, and cognition [52], these studies were not restricted to individuals with MCI or persons with sleep disturbance. Our study focuses on a high-risk population and examines associations between Vitamin D supplementation across dose categories and global cognition. Notably, only the highest dosage category (5000+ IU/day) was significantly associated with better overall cognitive performance, suggesting that higher reported supplementation levels may be linked to better cognitive outcomes in this co-morbid population. Direct work integrating Vitamin D dosage, sleep disturbance, and MCI remains limited, and the present study represents an important step towards addressing this gap.

4.1. Limitations and Strengths

To our knowledge, this exploratory study is the first to investigate the effects of Vitamin D supplementation on cognition in a population with both sleep disturbance and MCI. By assessing both Vitamin D type and dosage ranges on cognition, the results of this study extends the current literature on Vitamin D supplementation. A strength of our study is the use of validated sleep and cognitive questionnaires. Vitamin D intake was also assessed using standardized FFQ ranges [25].

Limitations of this study were its small sample size. Thus, these findings are considered preliminary and necessitate replication in larger sample sizes. Additionally, Vitamin D supplement intake was self-reported, and did not include any objective measures of Vitamin D levels. An important next step would be assessing circulating serum 25(OH)D levels to determine whether higher reported supplementation levels correspond to higher vitamin D status across increasing dose categories. Additional measures of pro- and anti-inflammatory markers will offer insight into the underlying mechanisms. Importantly, reverse causation cannot be excluded as individuals with better cognitive functioning may be more health-conscious and have higher-dose supplementation regimens. Further, the cross-sectional design and focus on older adults with both MCI and sleep disturbances may limit generalizability to broader populations.

5. Conclusions

This study found that, among individuals with both MCI and sleep disturbances, only those reporting daily intake of high dosages of Vitamin D (5000+ IU) was associated with better cognitive performance. The current Recommended Dietary Allowance (RDA) guidelines for vitamin D is at least 600 IU/day for adults 50–70 and for adults older than 70, the daily requirement is at least 800 IU/d, with a tolerable upper intake level of 4000 IU/d for everyone older than 8 years [53]. Vitamin D toxicity may result in hypercalcemia, although most cases resolve without serious complications or sequelae [53]. Recent studies of Vitamin D supplementation have employed a wide range of dosing strategies. One study examining the safety profile between Vitamin D3 doses of 400, 4000, and 10,000 IU/day in healthy men and postmenopausal women aged 55–70 years old found that clinical adverse events were balanced across each treatment group, although higher doses were associated with increased rates of hypercalciuria and mild, transient hypercalcemia [54]. Additionally, a recent review of Vitamin D studies suggests that a daily dose between 4000 and 6000 IU of Vitamin D supplementation to attain serum 25(OH)D levels between 40 and 70 ng/mL may result in greater protection against adverse health outcomes [55]. Lower 25(OH)D concentrations have been associated with the incidence of sleep disorders [56] and have been found to be significantly decreased in individuals with MCI and AD compared to healthy controls [57]. Encouraging older adults with MCI and sleep disturbances to consider natural food sources of vitamin D such as fatty fish, salmon, and mackerel may be helpful. Further, regular sunlight exposure is an important source for vitamin D synthesis, as ultraviolet B (UVB) radiation from sunlight triggers vitamin D production in the skin [58].

The observed association between higher BMI and better overall cognition performance highlights the need for further investigation into the underlying mechanisms. BMI may also be associated with a modified response to Vitamin D supplementation [59]. Future studies should consider exogeneous administration of Vitamin D in individuals with co-occurring MCI and sleep disturbances to examine their effects on cognitive outcomes.

Highlights:

• First study to link cognition and Vitamin D dosage in a co-morbid population

• Better cognition is associated with daily 5000+ IU daily Vitamin D intake

• Higher daily Vitamin D intake may impact persons with sleep disturbance and MCI