Dietary Supplements

Front matter

Dietary Supplements Ch allenges and Future Research Edited by A. Venketeshwer Rao and Leticia Rao Edited by A. Venketeshwer Rao and Leticia Rao Traditionally, nutritional supplements were limited to essential vitamins and minerals. However, in recent years, scientists have identified several biologically active compounds from plant and animal foods having beneficial health effects. Although technically they are not “nutrients,” they are referred to as phytonutrients, nutraceuticals, and functional ingredients due to their potential health benefits. Taking advantage of these scientific findings, manufacturers now include supplements in their commercial products. Recognizing the increasing role of nutritional supplements in the management of health, and as more new information becomes available, this book caters to the needs of consumers, health professionals, and regulatory agencies. It covers a range of topics in supplements, from definitions to sources to mechanisms of action to management of health and diseases as well as future challenges. This book is a valuable source of information in this important and fast-growing area of human health. Published in London, UK © 2023 IntechOpen © Pavel Gerasimenko / iStock ISBN 978-1-80356-206-3

Dietary Supplements - Challenges and Future Research Edited by A. Venketeshwer Rao and Leticia Rao Published in London, United Kingdom http:/ /dx.doi.org/10.5772/intechopen.95717 Edited by A. Venketeshwer Rao and Leticia Rao Contributors Maja Ergović Ravančić, Valentina Obradović, Paschal Chukwudi Aguihe, Ibinabo Imuetinyan Ilaboya, Deji Abiodun Joshua, Abdul Hei, Laishram Sanahanbi, Simon Welham, Lisa Coneyworth, Elizabeth Eveleigh, A. Venketeshwer Rao, Leticia Rao © The Editor(s) and the Author(s) 2023 The rights of the editor(s) and the author(s) have been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights to the book as a whole are reserved by INTECHOPEN LIMITED. The book as a whole (compilation) cannot be reproduced, distributed or used for commercial or non-commercial purposes without INTECHOPEN LIMITED’s written permission. Enquiries concerning the use of the book should be directed to INTECHOPEN LIMITED rights and permissions department (permissions@intechopen.com).

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Section 1 An Overview of the Role of Dietary Supplements in Human Health

Chapter 1 Introductory Chapter: Dietary Supplements, Definitions, Role in Human Health and Regulatory Issues A. Venketeshwer Rao and Leticia Rao 1. Introduction National dietary guidelines are the ideal way to meet all the nutritional requirements for a healthy life. However for genetic, health or lifestyle-related activities, not everyone can follow these dietary guidelines. Not following the dietary guidelines can result in individuals not being able to meet their nutritional requirements leading to health-related issues. In the belief that they may not be meeting the required levels of nutrients, either justified or not, they take ‘supplements’ as insurance towards nutrient adequacy and good health. A common understanding of dietary supplements is presented in Table 1. Figure 1 shows a typical dietary supplement fact of a commercial product [1]. Traditionally, the focus of dietary supplements is essential vitamins and minerals. However, in recent years, other biologically active components of foods have also been identified as playing an important role in human health [2, 3]. Although technically they are not ‘nutrients’ , they are referred to as ‘phytonutrients’ , ‘nutraceuticals’ , functional ingredients’ and ‘bioactive beneficial compounds. They include compounds such as carotenoids, polyphenols, dietary fibre and many more from plant and animal kingdoms. Nutritionists and other health professionals now believe that consuming these phytonutrients as part of a • A dietary supplement is a product that is manufactured with the aim of supplementing one’ s regular diet. They are not intended to treat, diagnose, prevent or cure diseases. • They are either natural compounds extracted from food sources or synthetic. • Traditionally they include vitamins and minerals in the form of multivitamin and mineral preparations. • May also contain fibre, amino acids and fatty acids. • May also contain other nonessential substances claimed to have beneficial health effects such as plant pigments, polyphenols and other biologically active compounds, including animal-derived compounds. • May also contain animal-derived compounds such as collagen. • They may be marketed individually or as a combination. • They often contain health claims such as supporting heart, brain, eye health and bone strength. Table 1.

Understanding what a dietary supplement is.

daily diet is beneficial to maintain good health and avoiding diseases. However, being a new area of research, in most cases, there are no recommended levels of their intake except to advise consumers to include foods that are good sources of these phytonutrients as part of their healthy diet. This concept of taking supplements has gained popularity in recent years. Recognising the potential for a business opportunity, business sectors around the globe are now offering a wide range of dietary and nutritional supplements. This increase in the intake and sales of supplements has raised serious concerns among health professionals and government regulatory agencies. Questions are now being raised regarding the validity of the scientific evidence in support of supplements and possible misuse leading to adverse effects. In view of the importance of the issue of dietary supplements, several review articles have been published over the years [4–8], and it was felt that there was a need for a book on this topic to provide current knowledge on the research that is being conducted and provide science-based opinions relating to the use of supplements. 2. Challenges and future research Undoubtedly, nutrient deficiencies such as vitamin A, iron, folic acid and vitamin D, to name a few , have been documented to affect the health of infants, children and childbearing women in the developing parts of the world. However, they are not restricted only to developing countries but also to industrialised countries. The reasons could include genetic factors, insufficient access to proper food, insufficient knowledge of nutrient requirements and their sources, and lifestyle factors. Dietary supplements, therefore, have a rightful place in providing the needed nutrients and other beneficial bioactive compounds to at-risk needy consumers. As a result, sales of these supplements have increased globally, indicating the awareness of the need for these compounds to maintain good health. However, there are still many challenges that the scientific community, consumers, manufacturers and regulatory agencies face in ensuring that the supplements being marketed and consumed are safe and indeed provide the healthy benefits claimed on the label [5]. As more and more new information is available relating to dietary supplements, one of the first challenges facing consumers and regulatory agencies is to define and understand what a dietary supplement is and differentiate them from medicines. Two important aspects of being considered are the intended use of the product and the claim(s) the product is associated with [6, 8]. In countries like the USA, Canada and Figure 1.

Typical dietary supplement facts of a commercial product [1].

Introductory Chapter: Dietary Supplements, Definitions, Role in Human Health and Regulatory… DOI: http://dx.doi.org/10.5772/intechopen.110644 Australia, dietary supplements are considered as being self-selecting with limited claims in support of overall health and wellness and not requiring a prescription from a medical practitioner [5]. However, these guidelines are not always universally applied and vary from country to country. As mentioned in their article by Dwyer et al. [5], melatonin is regulated in the USA as a dietary supplement, in Canada as a Natural Health Product (NHP), and in Australia as a prescription medicine. As more and more marketing of dietary supplements is becoming a global issue, a clear and well-defined definition is essential to minimise confusion. Another challenge is to have good science-based evidence in support of the claims that are often associated with dietary supplements. The two considerations that are important relate to the compound itself that is being evaluated and the design of the study being used. With respect to the compound itself, its source, purity and scientifically valid analytical procedures for its evaluation are important. With regard to the study design, if is absolutely essential that it is in accordance with scientifically accepted procedures of being double-blind with appropriate controls. If it is a clinical trial, the nature of the subjects participating, their health status, gender and age, length of administration of the compound being administered, procedures used to evaluate end results, and statistical procedures used in arriving at the results. In other words, the results derived from the study followed all the scientifically accepted procedures. In addition to the challenges mentioned above, one of the most important challenges is faced by the regulatory agencies [5]. Unfortunately, no one regulatory model is used globally based on their regional priorities and needs. However, one common consideration of the different regulatory models used globally is to assure the consumers that the dietary supplements are safe and meet the claims made by the manufacturers. We have come a long way in developing a regulatory framework to achieve the goals of safety and applicability. However, as more and more new compounds are now being identified as beneficial for good health and marketing, much more work needs to be done in the future.

This introductory chapter aims to provide readers with a better understanding of the need for dietary supplements, what they are and the challenges faced by the industry, consumers, scientists and regulatory agencies. The common goal of all these stakeholders is safety and good health.

Author details A. V enketeshwer Rao* and Leticia Rao University of Toronto, Toronto, Ontario, Canada * Address all correspondence to: venket.rao18@gmail.com © 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

References [1] Available from: https://www . mouseprint.org/2014/09/01/someonline-stores-make-shoppers-buyvitamins-blindly/ [2] Rao V . Phytochemicals. A Global Perspective of their Role in Nutrition and Health. London, UK: IntechOpen; 2012 [3] Rao A V , Manns D, Rao L, editors.

Phytochemical in Human Health.

London, UK: IntechOpen; 2020 [4] Abubakar AA et al. A review on dietary supplements: Health benefits, market trends, and challenges. 2020.

International Journal of Scientific Development and Research. 2020;5:26-34 [5] Dwyer JT , Coates PM, Smith MJ.

Dietary supplements: Regulatory challenges and research resources.

Nutrients. 2018;10:41-64 [6] Coates PM, Betz JM, Blackman MR, Crogg GM, Levine M, Moss J, et al., editors. Encyclopedia of Nutritional Supplements. 2nd ed. Boca Raton: CRC Press; 2010 [7] Journal of Dietary supplements.

Taylor and Francis. Available from: https://www .tandforline.com/journals/ ijds20 [8] US Food & Drug Administration.

What’ s New in Dietary Supplements.

Washington DC: US Food & Drug Administration; 2022

Section 2 Dietary Supplements in Health Management

Chapter 2 Supplements and Down Syndrome Maja Ergović Ravančić and V alentina Obradović Abstract Down syndrome (DS) is one of the most common genetic disorders associated with a number of difficulties that are visible through the motor and cognitive development. Some theories claim that intake of supplements in very high doses could upgrade the physical and intellectual status of individuals with DS. Numerous papers have been published to support these theories, but at the same time, a great number of papers have warned of the risks of uncontrolled, excessive use of dietary supplements and asked for the proof of such claims by independent scientific studies. In this chapter, we will provide a review of the most commonly used supplements and major findings on this matter. Open access to information about the positive and negative sides of such supplementation is primarily important for guardians of people with DS in order to make the decision whether to use such preparations. It could also be an incentive for scientists to focus on the development of beneficial and safe therapies. Keywords: Down syndrome, trisomy 21, oxidative stress, supplements, genes 1. Introduction The aim of this chapter is to provide the reader with scientifically based information about the possibilities and dangers of using nutritional supplements for individuals with Down syndrome (DS). DS or trisomy 21, first described by Dr. John Langdon Down in 1866, is one of the most common genetic disorders that impact fetal development.

It is a chromosomal disorder where an individual has an additional copy of chromosome 21, which may be full or partial [1]. The prevalence of children with DS worldwide is between 1:319 and 1:1000, and depends on the age of the mother (1/2000 in teenage girls to 1/40 in 42-year-old women) sociocultural, religious variables, and the possibility of terminating a pregnancy [2–4]. Every child with DS has unique phenotypic characteristics on which their overall physical and cognitive development depends, so the medical conditions associated with DS are not the same for every child (Figure 1). Considering the high cure rate of various comorbidities from which a DS child can suffer before and after birth, the mortality rate fell from 14.2% to 2.3% [5]. The life expectancy of people with DS has increased significantly over the last century, up to 60 years [6]. The use of nutritional supplements for children with DS is a topic that is extremely important for parents and caregivers as they want to improve their child's cognitive functions and health. However, the danger to the child can arise when the use of dietary supplements is uncontrolled, in large doses, and without a prior nutritional status of the organism. The program of early intervention with dietary supplements has been increasingly mentioned in connection with DS, however, research on the benefits of their use is still very unsupported by concrete evidence that would give doctors guidance for their recommendation. 2. Down syndrome Since the discovery that DS is a result of trisomy 21, the main interest of the studies has been the identification of human chromosome 21 genes (Hsa21), and the impact of their overexpression on the DS phenotype [7]. To explain the similarities and differences in the phenotypic characteristics associated with DS, a gene dose imbalance theory has been hypothesized stating that patients with DS have an increased dose or number of gene copies on Hsa21, which may lead to increased gene expression. This includes the possibility that specific genes or subsets of genes can control specific phenotypes of DS, but also that a nonspecific dose of a number of trisomic genes leads to a genetic imbalance that has a major impact on the expression and regulation of many other genes throughout the genome. Phenotypic analyzes found that only one or a few small chromosomal regions, termed “critical regions of Down syndrome, ” (DSCR) a region of 3.8–6.5 Mb at 21q21.22, with approximately 30 genes are responsible for most DS phenotypes [8, 9]. There are numerous physical features and congenital conditions specific to DS, resulting from overexpression of genes caused by the extra chromosome presented in Table 1. Every child is unique and features and conditions are not equally expressed and represented. Figure 1.

A three-year-old child with Down syndrome. (source: author).

Supplements and Down Syndrome DOI: http://dx.doi.org/10.5772/intechopen.106655 Promoting the health of people with DS is extremely important because it creates a prerequisite for improving their quality of life. Dietary composition, macronutrient and micronutrient intake, eating habits, and lifestyle can be fundamental for maintaining good health. Proper nutrition can have a major impact on preventing or delaying the onset of certain diseases in people with DS. However, very often nutrients from food are not enough to fulfill the daily needs for basic nutrients due to difficulties with swallowing and chewing, excessive sensory sensitivity, and numerous health problems, such as celiac disease. Cardiopathy in infants can impair food tolerance and adverse conditions may increase the frequency of aspiration [10]. In order to compensate for the lack of key nutrients necessary for the proper functioning of the body and fill the gap between diet and health in children with DS, dietary supplements can be used, but their usage should be controlled and in accordance with the identified deficiencies in the body. 3. History of nutritional supplementation for DS Based on the assumption that an extra chromosome causes a metabolic imbalance that can be affected by various dietary supplements, Dr. Henry Turkel developed Physical features Head Small, shortened skull that is flattened on the back, sloping forehead, missing or underdeveloped sinuses.

Eyes Upward slanted and wide-set eyes, brushfield spots, and epicanthal folds. Ears Ears set lower on the head and smaller ears with extra folds. Nose Smaller nose and flattened nasal bridge.

Mouth Smaller mouth, large tongue that tends to stick out more often, undersized teeth, crooked teeth, and irregularly shaped teeth.

Possible physical features and congenital conditions associated with Down syndrome [9].

the first formulation composed of 48 different substances called “U-series” in the 1940s. The Food and Drug Administration (FDA) rejected his request for a new drug because it could not serve as a cure. A modified supplement formula was developed by Dr. Jack Warner during the 1980s as high-performance capsules (HAP Caps), which contained high doses of dietary antioxidants, such as vitamins A, E, and C, digestive enzymes, minerals zinc (Zn), copper (Cu), manganese (Mn), and selenium (Se), in order to correct metabolic disorders. HAP caps were formulated in the FDA laboratory and had approval from 1986 until his death in 2004 [11, 12]. During this period, Dixie Lawrence Tafoya, combining elements of both treatments with the addition of new ingredients, developed a combination of targeted nutritional intervention (TNI) supplements that included amino acids and smart drugs (Piracetam) in addition to various micronutrients. These supplements were promoted under the name Nutrivene. In Canada, under the leadership of Kent Macleod, Nutrichem Laboratories has launched a supplement called "MSB Plus" in accordance with the standards of good manufacturing practice at the licensed Health Canada Site. Despite the fact that various supplements have been applied to children with DS since the 1950s, repeated studies have shown that there are no nutritional deficiencies that would apply to all children with DS. Furthermore, there is no objective study that has confirmed the need for any of these supplements, with the possible exception of the minerals Zn and Se [12, 13].

Sacks & Buckley [12] pointed out the lack of well-designed scientific studies and warned of the danger of overdose in the case of supplement introduction in addition to a balanced diet. Many studies that support supplementation involved a small number of subjects, a wide range of age participants, short duration, and very few randomized controlled and blind studies [14, 15].

The popularity of supplements was confirmed by a survey among 1,200 respondents in the US, Brazil, and the EU that found that almost half of pediatric patients with DS have used or are currently using dietary supplements. 20% of surveyed parents who gave their child supplements haven’t informed the pediatrician about it. Above all, supplements given to children with DS often exceeded the recommended daily doses [16]. Nevertheless, dietary supplements for DS still receive a lot of attention from parents, which leads to efforts of scientists to define the possible benefits of dietary supplements for people with DS-based on scientifically based knowledge. 4. DS issues targeted by nutritional supplementation 4.1 Oxidative stress The theory of oxidative stress involves the occurrence of oxygen radicals, called reactive oxygen species (ROS) during oxidative metabolism. ROS include superoxides (O2 •−) and hydroxyl (OH •) free radicals and other molecules, such as hydrogen peroxide (H2O2) and peroxynitrite which have the ability to become very harmful to cells. To defend against ROS, cells developed various mechanisms to eliminate them: antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)) along with antioxidants, such as vitamins C, E, or glutathione. If an imbalance between oxidants and antioxidants happens in cells, oxidative stress occurs [17 , 18]. Numerous studies point to oxidative stress as a possible explanation for a number of DS-related problems, such as intellectual disability, accelerated aging, and cognitive and neuronal dysfunction [14, 19–21].

Supplements and Down Syndrome DOI: http://dx.doi.org/10.5772/intechopen.106655 The 21st chromosome contains SOD1 gene, which encodes the enzyme Cu-Zn superoxide dismutase (Cu-Zn SOD), responsible for the conversion of O2− to H2O2 in the cytosol. Increased SOD1 activity results in the creation of elevated levels of H2O2 that should be effectively removed by other enzymes, such as CAT , GPx, and thioredoxin peroxidase. Excess of chromosomes leads to overexpression of the SOD1 gene, and to elevated H2O2 levels that cannot be completely eliminated by CAT and GPx, so overproduction of ROS occurs (Figure 2) [22–25]. SOD1 was found to be 50% higher than normal in various cells and tissues of people with DS, so the SOD1/GPx activity ratio was consequently altered [19, 22, 26–29].

Strydom et al. [30] in his study on 32 adults with DS could not confirm the hypothesis that an increased SOD1/GPx ratio leads to low cognitive results. Surprisingly, they found that a low SOD1/GPx ratio leads to bad memory ability. They also pointed out that other possible factors could also affect SOD1 and GPx activity, such as regular exercise, Se, and homocysteine levels. 4.2 Cognitive development Research has shown that the maturation of certain areas of the brain during childhood is associated with the development of specific cognitive functions, such as language, reading, and memory [31, 32]. Rapid brain growth occurs during the first 2 years of life (at age 2, the brain reaches 80% of an adult’ s weight), so this period of life may be particularly sensitive to nutritional deficiencies [33]. Nutrition, as the link between nutrients and health, should provide the building blocks needed to build and maintain the structure and function of the central nervous system. The intellectual disorder occurs when a child fails to fully develop the intellectual ability to think, reason, learn and understand. Children with intellectual disabilities also have problems in learning adaptive behavior, which encompasses the social and practical skills needed for everyday life. Intellectual impairment varies among children with Down syndrome. It ranges from a severe intellectual impairment that makes people completely dependent on caregivers, to mild effects that allow people to think and learn at levels that allow them to continue their higher education, keep their jobs, and live independently.

It is thought that nutrition may play a key role in brain development, and, thus intellectual functioning. The brain, similar to the rest of the body, needs proteins, fats, carbohydrates, vitamins, and minerals to grow and function, which are ingested through food or supplementation if food intake is difficult. As the brain develops faster than the rest of the body, it is obvious to consider that a lack of nutrition at Figure 2.

Oxidative stress in Down syndrome.

a critical stage of development can lead to permanent changes in the structure and functioning of the brain. In addition, the brain is the most metabolically active organ in the body, but it has very limited energy reserves, so it relies on a diet for a continuous supply of glucose. Similarly, minute-by-minute brain function requires an adequate supply of micronutrients that act as coenzymes or form structural parts of enzymes required for optimal metabolic activity [34, 35]. 4.3 Neurodegenerative diseases Since individuals with DS are prone to elevated levels of oxidative stress at an early age and consequent accumulation of ROS, which are cytotoxic byproducts of normal mitochondrial metabolism, there is an insufficient defense of endogenous antioxidants. In this case, oxidative molecules can disrupt cellular functions by affecting synaptic plasticity, ultimately leading to neuronal injury and apoptosis. Individuals with DS over the age of 35 have a higher frequency of short-term memory impairment and an increase in the rate of dementia, aphasia, and agnosia, while executive function impairments are evident as early as adolescence. One of the most important genes associated with DS is amyloid precursor protein (APP), a gene encoded on chromosome 21. Increased APP production may contribute in part to oxidative stress associated with neurodegenerative diseases and inflammation. Accumulation of amyloid-beta monomers can directly disrupt mitochondrial function resulting in reduced energy and accumulation of amyloid plaques leading to activation of inflammatory cascades [36, 37].

Alzheimer disease (AD) is a form of dementia that can most commonly develop in people with DS, as in the general population. Unfortunately, effective drugs have not yet been developed to be available to treat dementia in DS. Prevention is crucial to alleviate the symptoms of neurodegenerative diseases, but also to delay them. Detection of biomarkers and the development of sensitive cognitive screening tools will be essential for earlier diagnosis and better therapeutic management [38]. There are numerous studies on how to reduce or slow down the course of neurodegenerative diseases, such as AD, in people with DS. The causes of AD in people with DS is associated with overexpression of genes and lack of nutrients due to poor diet can be influenced by regulation of endogenous antioxidants, intake of vitamins, minerals, polyunsaturated fatty acids, and polyphenols [39–42]. 5. Commonly used nutritional supplements for individuals with Down syndrome 5.1 Vitamins As explained in the previous chapter, increased oxidative stress in individuals with DS is present from early life, leading to lipid peroxidation and DNA damage [43]. For that reason, antioxidant vitamins have been the focus of many research (Table 2). Vitamin E, especially its form known as α-tocopherol, is a strong antioxidant, important for the prevention of oxidation of unsaturated fatty acids in cell membranes [49, 50]. Some studies involved trisomy 16 mouse models in order to get a basis before clinical trials on DS humans because these mice have increased oxidative stress and cerebral pathology similar to DS [51–54].

Supplements and Down Syndrome DOI: http://dx.doi.org/10.5772/intechopen.106655 Lockrow et al. [43] suggested that transgenic mice could be used in order to get insight into the molecular pathways of the disease and to test the efficiency of drugs. They also warned that mice do not manifest all the features as humans do. Still, they proved a correlation between high oxidative stress in transgenic mice and low working memory. The introduction of vitamin E to the diet of mice gave positive results on oxidative stress and neuronal markers. They also suggested that this could be a good starting point for the treatment of neurodegenerative diseases, such as DS and AD, in humans. Lott [55] pointed out that clinical studies on humans still did not provide satisfactory results, although animal studies in oxidative stress are promising. As presented in Table 2, studies on humans had very different experimental groups in the number of participants, age, and dosage of supplements. The conclusions they Experimental group Vitamin Duration of trial Result Ref. Randomized, placebo-controlled study, 20536 adults aged 40–80 600 mg/day vitE 250 mg/day vitamin C 20 mg/day of carotene 5 year treatment period No improvement in cognitive abilities, no significant differences in all-cause, and vascular and non-vascular mortality. 93 children with DS aged 7–15 years, 26 non-DS siblings in the same age range as a control group 400 IU vitamin E 4 months No change in TBARS levels and reduced 8-OHdG levels.

Randomized double-blind study, 53 individuals with DS 900 IU α-tocoferol, 200 mg ascorbic acid, 600 mg α-lipoic acid 2 years No improvement or stabilisation of dementia. 5092 elderly people (90% aged 65 years and older) Various combinations of vitamin E, C, and multivitamins 3 years Combination of vitamins gave positive results in prevalence of Alzheimer's disease. 156 infants aged under 7 months with trisomy 21 100 mg vitamin E, 0 mg vitamin C, 0,9 mg vitamin A, 10 μg Se, 5 mg Zn, and 0,1 mg folinic acid 18 months No effect on SOD, GPx activity and SOD/GPx ratio, no effect on Griffiths developmental quotient, and an adapted MacArthur communicative development. 21 children with DS, 18 healthy children 400 mg vitamin E, 500 mg vitamin C 6 months Decrease of erythrocytic SOD and CAT , and decrease of GPx activity in DS children. 160 adults with trisomy 21 and 160 healthy, unrelated subjects aged 26 ± 4 years 5 mg/day folic acid, 5 mg/day vitamin B6, 100 μg/day B12 alone or in combination – No significant differences in fasting blood tHcy concentrations between healthy controls and adult trisomy 21 patients that justify B vitamin supplementation.

Table 2.

Examples of vitamin supplementation research for DS individuals.

obtained were also very different. Lockrow et al. [43] and Lott [55] suggested that vitamin E supplementation could exhibit better results if implemented at younger age as preventive therapy for dementia, but it requires additional clinical trials. Tanabe et al. [56] could not find a correlation between elevated Cu-Zn SOD activity and cellular vitamin E status in DS.

It can be seen that a combination of vitamins E and C have been commonly used. Vitamin C helps to maintain a stable concentration of vitamin E in plasma by protecting it from damaging oxidation and keeping it in the active state [49, 57 , 58]. The link between cognitive decline in AD and vitamin C intake has been studied by Harrison [18]. He included many studies involving vitamin C or a combination of vitamin C and E in his review article. Contradictory results regarding the usefulness of high doses of vitamin C for the cognitive decline have been provided, but a high connection between the low consummation rate of fruits and vegetables and bad cognitive function has been undoubtfully proved. So, prevention of deficiency by quality nutrition should be the first line of defense against cognitive decline instead of supplementation.

It is very important to remember that high doses of supplements can lead to organ damage, harmful interactions, and toxicity [59]. Besides, reactive oxygen species are necessary for obtaining normal cell functioning, so implementation of high doses of antioxidant supplementation would remove too much ROS disrupting cell signaling pathways [60, 61]. The dietary institute for medicine recommends 22 IU RDA for vitamin E and 75 to 90 mg for vitamin C, which is much lower than the doses usually present in supplements (up to 1000 IU of vitamin E and up to 1000 mg of vitamin C) or which have been used in previously mentioned studies [62]. The deficiency of B12 vitamin is mainly associated with a vegetarian and vegan diet, since it mainly originates from animal products. B12 deficiency in infants can lead to various clinical symptoms, such as hypotonic muscles, involuntary muscle movements, apathy, cerebral atrophy, and demyelination of nerve cells [63, 64]. It has an important role in brain function and development through methylation reactions in the central nervous system. Vitamin B12 is also a cofactor in numerous catalytic reactions in the human body, which are required for neurotransmitter synthesis and functioning. Vitamin B12 deficiency can also result in neuropathy through degeneration of nerve fibers and irreversible brain damage [65]. Folates are also B group, water-soluble vitamins, which serve as coenzymes in a variety of reactions. Numerous enzymes involved in folate transport and metabolism are encoded by genes located on chromosome 21 and represent a potential mechanistic basis for folate dysregulation in children with DS. Potential genetic causes of metabolic folate dysregulation in children with DS, non-genetic factors, such as diet, gender, and age, must be considered because they must fully satisfy their folate needs through their diet since they lack the enzymatic machinery necessary to synthesize their own. There are two possible mechanisms for the influence of folate and vitamin B12 deficiency on the brain: by disrupting myelination or influencing the inflammatory process [66, 67]. Individuals with DS have higher plasma homocysteine concentration than healthy people. There are several possible reasons for changes in its metabolism. The deficiency of vitamin B6, B12, and folic acid is one of the theories explaining the accumulation of homocysteine because those vitamins are important cofactors for its metabolism. High plasma concentration is a result of a high cytotoxic intracellular homocysteine. It is assumed that this is a repercussion of gene overexpression on chromosome 21 [68, 69]. Studies [14, 70–73] proved that intake of high doses of B group vitamins reduced homocysteine levels and reduced the rate of brain atrophy in