EFFECTS OF VITAMIN D3 COMBINED WITH FOLIC ACID ON DOMAIN AND SPECIFIC COGNITIVE FUNCTION AMONG PATIENTS WITH MILD COGNITIVE IMPAIRMENT: A RANDOMIZED CLINICAL TRIAL

 

W. Liu^2,*, D. Zheng^1,*, X. Li¹, T. Wang¹, L. Wang¹, L. Hao¹, M. Ju¹, W. Feng¹, Z. Guo¹, X. Sun¹, H. Yu¹, Z. Qin³, R. Xiao¹

 

1. School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; 2. Beijing Tongren Hospital, Affiliated to Capital Medical University, Department of Clinical Nutrition, No. 1 Dongjiaomin Alley, Dongcheng District, Beijing, 100730, China; 3. Jincheng People’s Hospital, Jincheng Shanxi 048000, China; * Co-first authors: Wen Liu and Deqiang Zheng are co-first authors of the article

Corresponding Author: Rong Xiao, School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China, xiaor22@ccmu.edu.cn

J Prev Alz Dis 2024;
Published online September 25, 2024, http://dx.doi.org/10.14283/jpad.2024.165

 

---

Abstract

INTRODUCTION: To investigate the effect of vitamin D3 (VD3) combined with folic acid (FA) intervention on the cognitive function among patients with mild cognitive impairment (MCI) and vitamin D deficiency.
METHODS: Our study is a single-center, randomized, controlled trial. A total of 402 patients were randomly assigned to the placebo group (n=135), FA group (n=134), and FA+1600IU VD3 group (n=133). The intervention period was 24 weeks. The primary endpoint was the mean change in Montreal Cognitive Assessment (MoCA) compared to baseline. Secondary endpoints included other cognitive functions, serum vitamin D, folic acid, and homocysteine levels.
RESULTS: The Intention-to-Treat analysis results of MoCA showed that the adjusted Least Squares Means (LSM) differences between the FA+1600IU VD3 group and the placebo or FA group were 0.456 (95% CI -0.198 to 1.11; p=0.171) and 0.038 (95% CI -0.600 to 0.676; p=0.907), respectively, and the Per-protocol set analysis results showed that the adjusted LSM differences between the FA+1600IU VD3 group and the placebo or FA group were 0.659 (95% CI 0.005 to 1.313; p=0.048) and 0.251 (95% CI -0.387 to 0.889; p=0.44), respectively.
CONCLUSION: The effect of FA+1600IU VD3 intervention for 6 months on overall cognitive function in MCI patients with vitamin D deficiency was not significant, but its role may be underestimated and requires further long-term studies to confirm.

Key words: Vitamin D, folic acid, mild cognitive impairment, randomized controlled trial.

Abbreviations: 25(OH)D: 25-hydroxyvitamin D; AD: Alzheimer’s disease; AVLT: Auditory Verbal Learning Test; AVLT: Auditory Verbal Learning Test; AVLT-IR: AVLT-immediate recall; AVLT-LR: AVLT-long recall; AVLT-SR: AVLT-short recall; BMI: Body mass index; FA: folic acid; FFQ: food frequency questionnaire; FOL: folate; Hcy: homocysteine; ITT: Intention-to-Treat Analysis; MCI: mild cognitive impairment; MMSE: Minimum Mental State Examination; MoCA: Montreal Cognitive Assessment; PP: Per-protocol; SCWT-RIE: Stroop Colour-Word Test-Interference Trial-reaction interfered effects; SCWT-TIE: SCWT-time interfered effects; SDMT: Symbol Digit Modalities Test; TMT: Trail Making Test; VD3: vitamin D3.

---

 

Introduction

Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients often exhibit multiple nutrient deficiencies. Vitamin D deficiency is a risk factor for AD/MCI, but evidence that vitamin D intervention can improve cognitive measures is insufficient (1-3); Folate deficiency can lead to hyperhomocysteinemia, which can aggravate oxidative stress in brain tissue and damage neurons. FA can suppress the oxidative stress response in brain tissue by reducing the level of homocysteine (Hcy), thus improving cognition (4). Two randomized controlled intervention studies from China show that there was a beneficial effect from relatively short-term folate supplementation on cognitive functioning in later life (5, 6), however, a two-year FA and vitamin B12 (combined with 15μg vitamin D3) supplementation did not beneficially affect performance on 4 cognitive domains in elderly people (7). Further studies are thus needed to confirm the effect of vitamin D combined with FA on cognitive function, and our study is the first study to investigate the combined effects of vitamin D3 and FA on cognition in MCI.
The main objective of the present study was to determine whether vitamin D combined with FA affects cognition by regulating serum levels of 25-hydroxyvitamin D [25(OH)D] and folate (FOL). The results of this study provide new insights into the prevention and treatment of AD/MCI from the perspective of nutrition.

 

Methods

Participants

Participants were recruited from a cohort entitled the Effects and Mechanism Investigation of Cholesterol and Oxysterol on Alzheimer’s Disease (EMCOA) (8) cohort, Inclusion criteria were male or female aged 50 to 70 years who meet the following: (1) MCI patients as determined using the Minimum Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) according to the Petersen/Winblad criteria (impairment in one neuropsychological score defined as at least 1.5 standard deviations (SD) below normative expectations) (9), with suspected MCI patients were then diagnosed by neurologists to establish a clinical diagnosis (10); (2) patients who did not take supplemental vitamin D, FA, vitamin B12, or other health products or drugs to improve cognition, or voluntarily stopped taking these nutritional interventions or drugs 3 months before the intervention; and (3) serum 25(OH)D <50nmol/L (11). Patients who did not meet the inclusion criteria but were suffering from other diseases or conditions that could affect cognitive function (e.g., depression, Parkinsonism, cerebral vascular disease), or had malignancy or other severe illnesses, such as coronary heart disease, were excluded, The recruitment flow chart is shown in Figure 1. This study was registered at the Chinese Clinical Trial Registry as ChiCTR1900025452. All participants gave written informed consent to participate in this study, which was approved by the Ethics Committee of Capital Medical University (No. 2013SY35).

Experimental design

In this study, subjects were recruited and enrolled from November 2020 to January 2021. The intervention period was 6 months; a nutritional intervention was given by researchers every 2 months, at which time the remaining drugs were recovered and counted. A computer-generated random number was used to randomly divide the patients into three groups, each participant had an equal probability of being assigned to either the experimental group or the control group. Participants were asked to take either a vitamin or a placebo pill orally with a meal at breakfast. In the placebo group, participants were asked to take 2 soybean oil capsules (exhibiting the same characteristics as vitamin D3 [VD3] capsules) and 1 starch tablet (exhibiting the same characteristics as FA tablets) once each day. In the FA group, participants were asked to take 1 soybean oil capsule and 1 FA tablet (400 μg) once each day, and in the 1600IU VD3 combined with FA group, participants were asked to take 2 VD3 capsules (1600 IU) and 1 FA tablet (400 μg) once each day.

Intervention and placebo

VD3 and its placebo were processed and supplied by Sinopharm Xingsha Pharmaceuticals (Xiamen) Co., Ltd. VD3 capsules contained 800 IU each, and the placebo was a soybean oil soft capsule consistent in appearance. FA and its placebo were processed and supplied by Beijing Scrianen Pharmaceutical Co., Ltd. FA tablets contained 400 μg/tablet, and its placebo was a starch tablet with the same appearance, colour, and smell as the FA tablet.

Outcomes

The primary endpoint is the mean change in MoCA from baseline to 24 week. Secondary endpoints include changes in multiple specific cognitive function at week 24, as well as changes in serum levels of 25(OH)D, folate, and homocysteine. Global cognitive function was assessed using the MoCA, an 11-item cognitive test. Memory was assessed using the digit span test (DST), including the digit span forwards test (DSTF), digit span backward test (DSTB), and the Auditory Verbal Learning Test (AVLT), including the AVLT-immediate recall (AVLT-IR), AVLT-short recall (AVLT-SR), AVLT-long recall (AVLT-LR) from the Wechsler Memory Scale-Revised, Chinese version. Processing speed was assessed using the Symbol Digit Modalities Test (SDMT). Attention was assessed using the Trail Making Test (TMT) A and B, the Stroop Colour-Word Test-Interference Trial-reaction interfered effects (SCWT-RIE) and SCWT-time interfered effects (SCWT-TIE) tests. In all tests except the TMT and SCWT-TIE, a higher score indicated better performance.

Dietary assessment and covariates

Dietary surveys were conducted at baseline and after the intervention using a and a 3-day 24-hour dietary review questionnaire. Dietary nutrient intakes of FOL, vitamin D, and cholesterol were subsequently calculated from the collected data based on our previous study[9]. Social demographic information included age, gender, and education. Lifestyle included smoking status, alcohol consumption, and time spent outdoors. The time spent outdoors was split into three groups (time spent outdoors < 30, 30-60, or ≥ 60 min/d) groups, respectively. Body mass index (BMI) was calculated as weight (kg)/height (m)2, and patients were divided into three groups defined as lean (BMI <18.5 kg/m2), normal (BMI 18.5-23.9 kg/m2), overweight (BMI 24-27.9 kg/m2), and obese (BMI ≥28 kg/m2). Hypertension, diabetes, and other diseases were determined by self-report.

Laboratory methods

Venous blood samples for biochemical parameters were obtained in the morning after overnight fasting. Serum levels of 25(OH)D and FOL were measured using a Roche cobase e 602 electrochemiluminescence immunoassay analyser. Serum levels of Hcy were assessed using a Roche Hitachi 8000 C automatic biochemistry analysis system.

Statistics

The sample size calculation was based on the study (3). The minimum acceptable between-group difference is 0.1%, and the estimated standard deviation is 0.15%, with a two-sided α of 0.05 and β of 0.2. Therefore, each group requires 108 participants, considering a 20% dropout rate, resulting in a need for 135 participants per group. The primary endpoint will be analyzed using intention-to-treat (ITT) and safety analysis set (SS) analyses. The ANCOVA model will be used for the primary endpoint, calculating the LSM and 95% CI to compare the three groups’ primary endpoint (change in MoCA) and key secondary endpoints. The ANCOVA model adjusts for gender, age, education level, outdoor activity time, family history of diabetes, family history of hypertension, smoking status, alcohol consumption, and baseline MoCA values. Missing values for the primary and key secondary efficacy endpoints will be imputed using multiple imputation methods. Continuous variables will be described using mean ± standard deviation (SD) or median (interquartile range), while categorical variables will be represented using frequency and constituent ratio (%). For all analyses, a two-tailed P value <0.05 was considered to be statistically significant. All statistical analyses were performed using IBM SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and R 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria).

 

Results

A total of 548 participants were screened, of whom 146 were excluded. A total of 402 participants were finally enrolled and were randomly assigned to the placebo group (n=135), folic acid group (n=134), or the 1600IU VD3 combined with folic acid intervention group (n=133) (Figure 1). A total of 366 participants completed the 24-week intervention, with a completion rate of 91%.

There were 548 eligible subjects in this study, of which 402 subjects were randomly assigned to each intervention group.

 

The mean age of the patients was 62.58 years (SD 4.64), with males accounting for 42%. 52.5% of the participants had an education level of ≤6 years, 26.9% had an education level between 6 and 12 years, and 20.6% had an education level of >12 years. Among the 402 patients, 22.9% smoked and 8.3% consumed alcohol. 11.4% had outdoor activity time ≤30 minutes per day, 40.3% had outdoor activity time between 30 and 60 minutes per day, and 48.3% had outdoor activity time >60 minutes per day. The mean MoCA score was 23.38 (SD 2.95). The mean serum levels of 25(OH)D were 33.25 nmol/L, folate was 19.69 mmol/L, and Hcy was 20.85 μmol/L. Complete information on baseline characteristics can be found in the study (Table 1).

Data are n (%) or mean (SD) and include all patients in the full analysis set. Abbreviations: AVLT, Auditory Verbal Learning Test; DST, The digit span; FA, folic acid; Ref: Referent category; MoCA, Montreal Cognitive Assessment;SCWT-RIE, Stroop Color-Word Test-Interference Trial-reaction interfered effects; SCWT-TIE, SCWT-time interfered effects; SDMT, symbol digit modalities test;TMTA, Trail Making Test A; TMTB, Trail Making Test B; VD3, vitamin D3.

 

Domain-specific cognitive function

From baseline to week 24, the ITT analysis showed that the FA+1600 IU VD3 intervention group (0.819 [0.371]) had a greater increase in MoCA scores compared to the placebo group (LSM 0.363 [SE 0.376]) and folic acid group (0.781 [0.374]) (Figure 2A, Table 1). After adjusting for gender, age, education level, outdoor activity time, family history of diabetes, family history of hypertension, smoking status, alcohol consumption, and baseline MoCA values, the differences between the FA+1600 IU VD3 intervention group and the placebo group and folic acid group were 0.456 (95% CI -0.198 to 1.11; p=0.171) and 0.038 (95% CI -0.600 to 0.676; p=0.907), respectively, with no statistical significance according to the ITT analysis. However, when analyzing the patients who completed the 24-week treatment, the results showed that the differences between the FA+1600 IU VD3 intervention group and the placebo group and folic acid group were 0.659 (95% CI -0.005 to 1.313; p=0.048) and 0.251 (95% CI -0.387 to 0.889; p=0.44), respectively, with statistically significant differences according to the PP analysis (Figure 2B, eTable 1). From baseline to week 24, the ITT analysis showed that the difference in attention (TMTB) between the FA+1600 IU VD3 intervention group and the placebo group was -20.403 (95% CI -38.28 to -2.526; p=0.025), with no statistical significance compared to the folic acid group (p=0.835) (Table 2). However, there were no statistically significant differences in the decline from baseline in multidimensional cognitive function tests such as memory (AVLT and DST), processing speed (SDMT), and reaction (SCWT) (Table 2).

Data are adjusted LSM (SE). Data are n (%) or mean (SD) and include all patients in the full analysis set. Abbreviations: AVLT, Auditory Verbal Learning Test; DST, The digit span; FA, folic acid; Ref: Referent category; MoCA, Montreal Cognitive Assessment;SCWT-RIE, Stroop Color-Word Test-Interference Trial-reaction interfered effects; SCWT-TIE, SCWT-time interfered effects; SDMT, symbol digit modalities test;TMTA, Trail Making Test A; TMTB, Trail Making Test B; VD3, vitamin D3.

 

From baseline to week 24, the mean increase in serum 25(OH)D levels was greater with FA + 1600 IU VD3 intervention group (LSM 62.17 nmol/L [SE 3.971]) compared to placebo (38.408 [3.994]) and folic acid (28.493 [4.075]) groups. After adjustment, the LSM differences between the FA+1600 IU VD3 intervention group and placebo and folic acid groups were 23.762 nmol/L (95%CI 19.219 to 28.304; p<0.0001) and 33.676 nmol/L (95%CI 29.135 to 38.218; p<0.0001), respectively (Figure 2C; Table 2). From baseline to week 24, the mean decreases in serum Hcy levels were greater with FA+1600 IU VD3 intervention group (-3.195 [0.814]) and folic acid group (-3.665 [0.821]) compared to placebo (0.791 [0.837]) groups. After adjustment, the LSM differences in Hcy between the FA + 1600 IU VD3 intervention group and the placebo group were -3.986 μmol/L (95%CI -5.668 to -2.305; p<0.0001) (Figure 2D; Table 2).

(A) ITT analysis for domain cognitive function changes among three groups from baseline to 24 weeks intervention. (B) Completers analysis for domain cognitive function changes among three groups from baseline to 24 weeks intervention. (C) Changes of serum 25(OH)D levels from baseline to 24 weeks. (D) Changes in serum Homocysteine levels from baseline to 24 weeks.

 

One participant (0.007%) in the placebo group and FA + 1600IU VD3 group withdrew from the study due to a fall injury. One participant (0.007%) in the folic acid group was hospitalized for hypertension treatment, and one participant (0.007%) in the FA + 1600IU VD3 group was hospitalized for coronary heart disease treatment. No adverse reactions related to the use of placebo, folic acid, or vitamin D3 were observed in any group (Table 3).

 

Discussion

This study found that among individuals with vitamin D deficiency and MCI, those who completed high-dose vitamin D supplementation combined with folic acid had significantly improved overall cognitive function and attention (TMTB) compared to the placebo group. However, the ITT analysis showed no statistically significant difference in overall cognitive function change between the three groups, there was a ‘trend’ towards improved overall cognitive function.
Vitamin D insufficiency and deficiency are risk factors for AD/MCI, observational studies have shown that the risk of developing AD in persons with vitamin D insufficiency and deficiency is 1.19 and 1.31 times that of persons with vitamin D sufficiency, respectively (12-16). The effect of vitamin D intervention studies on cognitive function is not well defined, with studies finding no significant effect of long-term vitamin D supplementation on preventing the occurrence of AD or MCI (1, 17). Studies of vitamin D intervention for patients with MCI or AD have shown that vitamin D can significantly improve domain cognitive function and reduce serum levels of Aβ in those with MCI/AD (2, 18, 19). Our study results showed that after 24 weeks of vitamin D3 combined with folic acid intervention, the MoCA score changed by 0.251 and 0.659 compared to the folic acid alone intervention and placebo group, and the difference was statistically significant compared to the placebo group; while the ITT analysis showed that the MoCA score changed by 0.038 and 0.456 compared to the folic acid alone intervention and placebo group, and the difference was not statistically significant. These study results suggest that vitamin D3 combined with folate intervention has a better effect on overall cognitive function than folate alone intervention and placebo, but the results may be overestimated.
Serum levels of folate and Hcy are closely associated with the occurrence of AD and MCI. FA intake is a significant factor influencing serum levels of folate and Hcy (20, 21), daily supplementation with 0.5-5.0 mg FA can reduce plasma Hcy levels by approximately 16% to 39%, and the mean MMSE score is also significantly higher (22). The study suggested that the mechanism of B vitamins in improving cognitive function might involve decreases in serum Hcy levels, which in turn attenuated grey matter atrophy, reduced Aβ1-42 deposition, and alleviated neuronal cytotoxicity, thereby positively affecting domain cognitive function (23). Vitamin D receptor (VDR) is widely distributed in the brain, and has numerous effects on the nervous system. These effects include the regulation of key survival mechanisms such as neurotrophic factor production, regulation of oxidative stress, calcium homeostasis, and immune system functions (24, 25). Furthermore, vitamin D3 and VDR increase intestinal proton-coupled folate transporter expression, resulting in enhanced cellular folate uptake (26), which suggests that there may be a synergistic effect between vitamin D and folic acid. The mechanism by which vitamin D combined with folic acid affects cognitive function requires further research for confirmation.
Our study found that the FA +1600 IU VD3 group and FA group had a significant reduction in serum levels of Hcy than the placebo group after 24 weeks of intervention.
The innovation of this study is the effects of VD3 combined with FA intervention on cognitive function, which provided evidence and ideas for further research on the mechanism of VD3 combined with FA intervention on cognitive function. The limitation of this study is that with a follow-up time of only 24 weeks, it may be difficult to observe significant changes in cognition. Thus, the sample size should be increased and the intervention time extended so that AD outcomes could be observed, thereby verifying the results of this study.
In conclusion, for individuals with MCI and vitamin D deficiency or insufficiency, supplementing vitamin D and folate to improve the vitamin D deficiency state may improve overall cognitive function.

 

Acknowledgments: RX conceived and designed the study. WL and DQZ performed the analyses and wrote the manuscript. LXC helped analyze the data. TW, LJW, LH, MWJ, WJF, ZTG, XJS, HYY, and ZSQ helped collect the data. All authors read and approved the final manuscript. We appreciate Xiaoqin Zhong from Sinopharm Xingsha Pharmaceuticals (Xiamen) company and Zhengjun Cai from Beijing Scrianen Pharmaceutical company for their technical assistance.

Availability of data and materials: The datasets and analyzed during the current study are available from the corresponding author on reasonable request.

Funding statement: This work was supported by the National Natural Science Foundation of China (Grant No. 81973021), the State Key Program of the National Natural Science Foundation of China (Grant No. 81330065) and the National Natural Science Foundation of China (Grant No. 82173501).

Conflicts of interest: The authors declare that they have no competing interests.

Ethics approval and consent to participate: The protocol was approved by the Ethics Committee of Capital Medical University (No. 2013SY35) and was implemented in accordance with provisions of the Declaration of Helsinki and GoodClinical Practice guidelines.

 

SUPPLEMENTARY MATERIAL

 

References

1. Rossom RC, Espeland MA, Manson JE, Dysken MW, Johnson KC, Lane DS, LeBlanc ES, Lederle FA, Masaki KH, Margolis KL. Calcium and vitamin D supplementation and cognitive impairment in the women’s health initiative. J Am Geriatr Soc, 2012, 60(12): 2197-2205. doi:10.1111/jgs.12032
2. Hu J, Jia J, Zhang Y, Miao R, Huo X, Ma F. Effects of vitamin D(3) supplementation on cognition and blood lipids: a 12-month randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry, 2018, 89(12): 1341-1347. doi:10.1136/jnnp-2018-318594
3. Schietzel S, Fischer K, Brugger P, Orav EJ, Renerts K, Gagesch M, Freystaetter G, Stahelin HB, Egli A, Bischoff-Ferrari HA. Effect of 2000 IU compared with 800 IU vitamin D on cognitive performance among adults age 60 years and older: a randomized controlled trial. Am J Clin Nutr, 2019, 110(1): 246-253. doi:10.1093/ajcn/nqz081
4. Olaso-Gonzalez G, Inzitari M, Bellelli G, Morandi A, Barcons N, Vina J. Impact of supplementation with vitamins B(6) , B(12) , and/or folic acid on the reduction of homocysteine levels in patients with mild cognitive impairment: A systematic review. IUBMB Life, 2022, 74(1): 74-84. doi:10.1002/iub.2507
5. Chen H, Liu S, Ji L, Wu T, Ji Y, Zhou Y, Zheng M, Zhang M, Xu W, Huang G. Folic Acid Supplementation Mitigates Alzheimer’s Disease by Reducing Inflammation: A Randomized Controlled Trial. Mediators Inflamm, 2016, 2016(5912146. doi:10.1155/2016/5912146
6. Ma F, Wu T, Zhao J, Han F, Marseglia A, Liu H, Huang G. Effects of 6-Month Folic Acid Supplementation on Cognitive Function and Blood Biomarkers in Mild Cognitive Impairment: A Randomized Controlled Trial in China. J Gerontol A Biol Sci Med Sci, 2016, 71(10): 1376-1383. doi:10.1093/gerona/glv183
7. van der Zwaluw NL, Dhonukshe-Rutten RA, van Wijngaarden JP, Brouwer-Brolsma EM, van de Rest O, In ‘t Veld PH, Enneman AW, van Dijk SC, Ham AC, Swart KM, et al. Results of 2-year vitamin B treatment on cognitive performance: secondary data from an RCT. Neurology, 2014, 83(23): 2158-2166. doi:10.1212/WNL.0000000000001050
8. An Y, Zhang X, Wang Y, Wang Y, Liu W, Wang T, Qin Z, Xiao R. Longitudinal and nonlinear relations of dietary and Serum cholesterol in midlife with cognitive decline: results from EMCOA study. Mol Neurodegener, 2019, 14(1): 51. doi:10.1186/s13024-019-0353-1
9. Liu W, Zhou C, Wang Y, Yu H, Zhang X, Wang T, Wang L, Hao L, Qin Z, Xiao R. Vitamin D Deficiency Is Associated with Disrupted Cholesterol Homeostasis in Patients with Mild Cognitive Impairment. J Nutr, 2021, 151(12): 3865-3873. doi:10.1093/jn/nxab296
10. Zhang X, Wang Y, Liu W, Wang T, Wang L, Hao L, Ju M, Xiao R. Diet quality, gut microbiota, and microRNAs associated with mild cognitive impairment in middle-aged and elderly Chinese population. Am J Clin Nutr, 2021, 114(2): 429-440. doi:10.1093/ajcn/nqab078
11. Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Kostenberger M, Tmava Berisha A, Martucci G, Pilz S, Malle O. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr, 2020, 74(11): 1498-1513. doi:10.1038/s41430-020-0558-y
12. Duchaine CS, Talbot D, Nafti M, Giguere Y, Dodin S, Tourigny A, Carmichael PH, Laurin D. Vitamin D status, cognitive decline and incident dementia: the Canadian Study of Health and Aging. Can J Public Health, 2020, 111(3): 312-321. doi:10.17269/s41997-019-00290-5
13. Miller JW, Harvey DJ, Beckett LA, Green R, Farias ST, Reed BR, Olichney JM, Mungas DM, DeCarli C. Vitamin D Status and Rates of Cognitive Decline in a Multiethnic Cohort of Older Adults. JAMA Neurol, 2015, 72(11): 1295-1303. doi:10.1001/jamaneurol.2015.2115
14. Matchar DB, Chei CL, Yin ZX, Koh V, Chakraborty B, Shi XM, Zeng Y. Vitamin D Levels and the Risk of Cognitive Decline in Chinese Elderly People: the Chinese Longitudinal Healthy Longevity Survey. J Gerontol A Biol Sci Med Sci, 2016, 71(10): 1363-1368. doi:10.1093/gerona/glw128
15. Soares JZ, Valeur J, Saltyte Benth J, Knapskog AB, Selbaek G, Arefi G, Gilfillan GD, Tollisen A, Bogdanovic N, Pettersen R. Vitamin D in Alzheimer’s Disease: Low Levels in Cerebrospinal Fluid Despite Normal Amounts in Serum. J Alzheimers Dis, 2022, 86(3): 1301-1314. doi:10.3233/JAD-215536
16. Jayedi A, Rashidy-Pour A, Shab-Bidar S. Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response (dagger). Nutr Neurosci, 2019, 22(11): 750-759. doi:10.1080/1028415X.2018.1436639
17. Owusu JE, Islam S, Katumuluwa SS, Stolberg AR, Usera GL, Anwarullah AA, Shieh A, Dhaliwal R, Ragolia L, Mikhail MB, Aloia JF. Cognition and Vitamin D in Older African-American Women- Physical performance and Osteoporosis prevention with vitamin D in older African Americans Trial and Dementia. J Am Geriatr Soc, 2019, 67(1): 81-86. doi:10.1111/jgs.15607
18. Jia J, Hu J, Huo X, Miao R, Zhang Y, Ma F. Effects of vitamin D supplementation on cognitive function and blood Abeta-related biomarkers in older adults with Alzheimer’s disease: a randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry, 2019, 90(12): 1347-1352. doi:10.1136/jnnp-2018-320199
19. Yang T, Wang H, Xiong Y, Chen C, Duan K, Jia J, Ma F. Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial. J Alzheimers Dis, 2020, 78(4): 1509-1518. doi:10.3233/JAD-200926
20. Xu W, Tan L, Wang HF, Jiang T, Tan MS, Tan L, Zhao QF, Li JQ, Wang J, Yu JT. Meta-analysis of modifiable risk factors for Alzheimer’s disease. J Neurol Neurosurg Psychiatry, 2015, 86(12): 1299-1306. doi:10.1136/jnnp-2015-310548
21. Wang Q, Zhao J, Chang H, Liu X, Zhu R. Homocysteine and Folic Acid: Risk Factors for Alzheimer’s Disease-An Updated Meta-Analysis. Front Aging Neurosci, 2021, 13(665114. doi:10.3389/fnagi.2021.665114
22. Kaye AD, Jeha GM, Pham AD, Fuller MC, Lerner ZI, Sibley GT, Cornett EM, Urits I, Viswanath O, Kevil CG. Folic Acid Supplementation in Patients with Elevated Homocysteine Levels. Adv Ther, 2020, 37(10): 4149-4164. doi:10.1007/s12325-020-01474-z
23. Smith AD, Refsum H, Bottiglieri T, Fenech M, Hooshmand B, McCaddon A, Miller JW, Rosenberg IH, Obeid R. Homocysteine and Dementia: An International Consensus Statement. J Alzheimers Dis, 2018, 62(2): 561-570. doi:10.3233/JAD-171042
24. Gezen-Ak D, Dursun E. Vitamin D, a Secosteroid Hormone and Its Multifunctional Receptor, Vitamin D Receptor, in Alzheimer’s Type Neurodegeneration. J Alzheimers Dis, 2023, 95(4): 1273-1299. doi:10.3233/JAD-230214
25. Keeney JTR, Forster S, Sultana R, Brewer LD, Latimer CS, Cai J, Klein JB, Porter NM, Butterfield DA. Dietary vitamin D deficiency in rats from middle to old age leads to elevated tyrosine nitration and proteomics changes in levels of key proteins in brain: implications for low vitamin D-dependent age-related cognitive decline. Free Radic Biol Med, 2013, 65(324-334. doi:10.1016/j.freeradbiomed.2013.07.019
26. Eloranta JJ, Zair ZM, Hiller C, Hausler S, Stieger B, Kullak-Ublick GA. Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol, 2009, 76(5): 1062-1071. doi:10.1124/mol.109.055392

© Serdi 2024