INTRODUCTION
With aging poplation, dementia is becoming an increasing global problem. Alzheimer's disease is the most common form of dementia in the elderly and accounts for 60-80% of cases (1). Therefore, a growing interest in research into the prevention and treatment of dementia is justified. In this context, the use of vitamin D has been investigated for a long time. Below is an overview of currently available evidence on the effectiveness of vitamin D in this indication.
WHY IS VITAMIN D IMPORTANT?
Vitamin D is a vitamin that is synthesized in the skin after exposure to sunlight. After binding to the receptor, dihydroxy-vitamin D further participates in the expression of a number of genes involved in bone development and other functions. It's in vitro effect has been studied in many diseases. In addition to its effect on bone, vitamin D is also linked to the functioning of the immune system, and has been studied in the prevention and treatment of cardiovascular diseases and malignancies. Vitamin D deficiency has been associated with risk of developing immune diseases, neurological diseases (multiple sclerosis) and infections (especially respiratory) including COVID-19. But the American Food and Nutrition Board (FNB) concludes that the evidence for any effect attributed to vitamin D, other than a positive effect on bone health, is insufficient or contradictory. Due to its positive effect on bones, it is recommended that all adults take sufficient daily doses of vitamin D, preferably with food. The Recommended Daily Intake (RDA) of vitamin D is 600 IU (International Units; 15 mcg) in adults up to the age of 70. For persons older than 70, the RDA is 800 IU (20 mcg), but may be even higher (2). For pregnant and lactating women, the RDA is 600 IU (15 mcg). The optimal serum concentration of vitamin D for maintaining bone health is controversial, but according to the literature it is between 50 and 100 nmol / L. Levels below 30-50 nmol / l are considered deficient and <30 insufficient. The optimal serum concentration for other indications is not known.
SIDE EFFECTS OF HIGH DOSES OF VITAMIN D
Daily vitamin D intake of more than 4,000 IU in healthy individuals is generally not recommended. In patients with malabsorption (eg, celiac disease, gastrectomy, inflammatory bowel disease), the recommended doses will depend on the patient's ability to absorb vitamin D; high doses ranging from 10,000 to 50,000 IU are usually given. However, possible signs of toxicity should be monitored in these patients. Symptoms of toxicity are usually described at doses greater than 60,000 IU and are attributed to hypercalcemia and include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness (3). Chronic intoxication can cause nephrocalcinosis, bone demineralization, and pain.
VITAMIN D AND PREVENTION OF DEMENTIA
Vitamin D deficiency is being investigated as a possible risk factor for the development of dementia (4). The brain has the ability to synthesize the active form of vitamin D (1.25 hydroxyvitamin D) within many cell types and brain regions, predominantly in the hypothalamus and the large neurons within the substantia nigra. Many genes important in the production of responses to routine signals and stimuli are regulated by vitamin D. Functionally, vitamin D plays a role in neuroprotection by modulating the production of nerve growth factor, neurotrophin, glial cell neurotrophic factor, nitric oxide synthase, and actylcholine transferase. But knowing the importance of vitamin D for the normal functioning of the organism does not automatically mean that its application in deficient conditions would be clinically useful. Such conclusions can only be drawn on the basis of evidence from properly designed randomized controlled trials with sufficient subjects involved, if available. There is some evidence that vitamin D deficiency is associated with cognitive deficits in the elderly but the clinical significance of this is unknown. One meta-analysis and systematic review included 37 studies with a comparative group (5). The majority of the studies included were cross-sectional studies, followed by controlled case studies and cohort studies (two), and only 3 studies were randomized controlled studies (highest level of evidence), but with a relatively small number of patients involved. The number of subjects included ranged from 27 to 17,099, and most included subjects older than 65. Studies included patients with Alzheimer's and other dementias. All studies determined the level of vitamin D (1.25 hydroxyvitamin D). Most studies used MMSE (Mini-Mental State Examination) as a test of cognitive function. In most studies, the relationship between vitamin D and cognitive function was determined by comparing vitamin D concentrations between patients diagnosed with dementia and controls, or the result of cognitive function tests between groups with different vitamin D concentrations.
The main objections to the quality of the studies included in this meta-analysis were the process of blinding participants, selection of subjects, lack of adjustment for age and gender in results analysis, lack of knowledge on the methodology used in determining vitamin D levels, lack of knowledge on methods used for handling missing data. One of the main objections was the lack of data on the knowledge of the patient's cognitive status assessor about his vitamin D status. Thus, the included studies differed in the number of subjects, design, cognition tests used, methodology for determining vitamin D levels and patient grouping. It is therefore not surprising that a statistically significant heterogeneity was found between the included studies (cross-sectional studies and case studies with controls were included in the meta-analysis) regarding the evaluation of differences in vitamin D levels [mean difference was −15.0 nmol / L 25 (OH) D [−26.2, −3.9)] as well as in the evaluation of differences in MMSE results [mean difference in MMSE results was 1.2 (0.5, 1.9)] between the compared groups. For those less familiar with the meta-analysis methodology, statistically significant heterogeneity points to significant differences between the included studies that do not allow valid conclusions to be drawn from the obtained meta-analysis results (6).
Although the heterogeneity of the included studies was significant in this meta-analysis, its results suggested a possible association between vitamin D levels and cognitive impairment, but this effect appears to be modest, if any, and of unknown clinical significance. As previously mentioned, three randomized controlled clinical trials were included in the systematic review. The intervention in 2 of the 3 randomized controlled clinical trials was the administration of a multivitamin preparation that also contained vitamin D, and in only one placebo-controlled study the intervention was the administration of 9,000 IU of vitamin D2 over 8-40 weeks; no significant differences in cognitive outcomes were observed in this study. However, it should be noted that the number of included patients was small (n = 82). Most of these studies did not take into account the variability in vitamin D status. In addition, people with cognitive impairment have a higher risk of malnutrition and spend less time outdoors. Due to these objections, it is impossible to exclude reverse causality as an alternative explanation of the study results (dementia as a cause of vitamin D deficiency, and not vice versa). Two previously published meta-analyzes found no significant association between 1.25 hydroxyvitamin D levels and dementia (7.8). Whether vitamin D supplementation in healthy individuals or those with vitamin D deficiency reduces the risk of cognitive decline or dementia is unclear, but limited evidence does not support this. For valid conclusions, we need the results of controlled randomized intervention studies with a sufficient number of patients included. Meanwhile, due to the lack of evidence of its usefulness, prescribing vitamin D to prevent dementia is not recommended.
OTHER INTERVENTIONS IN PREVENTION OF DEMENTIA
In general, physical activity, social interaction, and cognitive activities are recommended for all patients, especially those at risk for developing dementia. Timely and good treatment of hypertension is especially important because of the proven association with an increased risk for vascular dementia and Alzheimer’s disease (9). Although a healthy diet is associated with positive health outcomes, including cognitive health, the evidence is insufficient to conclude that specific dietary regimens or dietary supplements are useful in reducing the risk of developing dementia. This applies to the use of omega-3 fatty acids, the Mediterranean diet and small amounts of alcohol. Prospective and randomized controlled clinical trials have not shown the benefit of the use of vitamins, statins, cholinesterase inhibitors, estrogen substitution, or the use of nonsteroidal antirheumatic drugs in the prevention of dementia.
OTHER VITAMINS Multivitamin preparations have not shown efficacy in preventing dementia or slowing cognitive decline in dementia (10,11). Despite some evidence that elevated serum homocysteine levels and / or decreased folate, vitamin B6, and vitamin B12 levels may be associated with cognition impairment and dementia risk, there is no convincing evidence from clinical trials of the benefit of vitamin use in dementia prevention (12,13). Although vitamin E has not been shown to be useful in preventing dementia, it may have limited benefit in slowing the progression of mild to moderate Alzheimer's disease (14,15). However, data from randomized studies are ambiguous (16). As high doses of vitamin E have been consistently associated in clinical trials with increased mortality and heart failure in patients with cardiac disease, the use of vitamin E in the prevention of dementia and for other forms (except mild to moderate Alzheimer's disease) of dementia is not recommended.
CONCLUSION
The only proven beneficial effect of vitamin D is its effect on bone health. In other indications in which the effect of vitamin D supplementation has been investigated, clinical trials do not provide solid evidence to justify recommendations for its use. These include the prevention and treatment of dementia, cardiovascular disease, multiple sclerosis, malignancies and infections including COVID-19. Evidence for the effect of vitamin D on the prevention of dementia is qualitatively modest, but does not provide justification for routine prescribing of vitamin D in this indication. The only evidence-based indication for prescribing vitamin D is deficiency / insufficiency and the use of recommended doses in the prevention of osteoporosis.
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