Supplement*	Route	Biological plausibility
Vitamins
Vitamin A	antioxidant; anti‐inflammatory; anti‐cholinesterase; beta‐amyloid inhibition	Carboxylic form of Vitamin A known as all‐trans retinoic acid has been shown to have memory restorative function and it may be attributed to its anti‐cholinesterase, anti‐oxidative and anti‐inflammatory potential (Sodhi 2013). Vitamin A and ß‐carotene may also inhibit the formation, extension and destabilising effects of beta‐amyloid fibrins. Plasma or cerebrospinal fluid concentrations of vitamin A and beta‐carotene have been reported to be lower in AD patients, and increased Vit A/beta carotene concentrations have been clinically shown to slow the progression of dementia (Ono 2012).
Vitamin D	neuronal activity	Vitamin D receptor (VDR) and 1, alpha‐hydroxylase, the terminal calcitriol‐activating enzyme, are distributed throughout both the foetal and adult brain. This is thought to play a role in brain development and critical brain functions (McCann 2008). Significant correlation between serum 25(OH)D levels and cognitive scores were reported in DeLuca 1975 and Przybelski 2007.
Vitamin E	antioxidant; beta‐amyloid inhibition	Vitamin E consists of a group of tocopherols and tocotrienols. Apart from lipid antioxidant activity, other functions include membrane stabilisation by forming complexes with the products of lipid hydrolysis (Wang 2000). It has been shown that the antioxidant and free radical scavenging activity of Vitamin E inhibits amyloid beta protein induced neuronal cell death and may have implication in prevention and treatment of Alzheimer’s dementia (Behl 1992).
Vitamin K	neuronal activity	Vitamin K participates in the synthesis of sphingolipids. Sphingolipids participate in important cellular events such as proliferation, differentiation, senescence, and cell‐cell interactions. Sphingolipid metabolism has been linked to age‐related cognitive decline and neurodegenerative diseases such as Alzheimer's disease (Ferland 2012). A cross‐sectional study found correlations between higher serum phylloquinone concentration and better cognitive scores in tests evaluating episodic verbal memory among healthy older adults (Ferland 2013).
Thiamine (Vitamin B1)	neuronal activity	Thiamine is required as a cofactor in the cellular production of energy and enhances normal neuronal activities (Osiezagha 2013). Rats with an episode of induced thiamine deficiency had cognitive, learning, and memory impairments (Langlais 1995).
Riboflavin (Vitamin B2)	neuronal activity	Riboflavin (7,8‐dimethyl‐10‐ribityl‐isoalloxazine) is water‐soluble. Symptoms of neurodegeneration and peripheral neuropathy in riboflavin deficiency have been documented in animal studies, but not observed in humans. Subclinical riboflavin deficiency may contribute to increased concentrations of plasma homocysteine and may be associated with increased risk of cardiovascular disease and impaired handling of iron (Powers 2003).
Niacin (Vitamin B3)	vascular: anti‐inflammatory	Niacin is a water‐soluble precursor cofactor essential for the formation of dozens of enzymes. Niacin decreases atherosclerosis development mainly by reducing LDL cholesterol. It also has modest HDL‐cholesterol‐raising and anti‐inflammatory effects (Kühnast 2013). Niacin deficiency causes pellagra. Its neuropsychiatric symptoms are similar to those in Alzheimer's disease or vascular dementia (Amanullah 2010).
Vitamin B6 (Pyridoxine, pyridoxal, pyridoxamine, Pyridoxal 5' phosphate (PLP) and pyridoxamine 5' phosphate (PMP), Pyridoxine 5'‐phosphate (PNP))	homocysteine; neuronal activity	Vitamin B6 is a group of water‐soluble compounds (vitamers). Pyridoxal 5' phosphate (PLP) and pyridoxamine 5' phosphate (PMP) are the active coenzyme forms of vitamin B6 (ODS 2014). Vitamin B6 has many important brain functions such as biosynthesis of neurotransmitters (GABA, dopamine, noradrenaline, serotonin), receptor binding, macronutrient metabolism, and gene expression. In a study looking at low plasma B6 levels predicting cognitive decline and depression in at‐risk individuals, low PLP status was seen as a risk factor for cognitive decline and depression in at‐risk populations (Scott 2013).
Folic Acid (Vitamin B9)	antioxidant; homocysteine; neuronal activity	Folate is a cofactor and promotes the remethylation of homocysteine ‐‐ an amino acid that can induce DNA strand breakage, oxidative stress, and apoptosis. Folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Folate deficiency and its resultant increase in homocysteine levels has been linked to several neurodegenerative conditions, including stroke, Alzheimer's disease, and Parkinson's disease (Mattson 2003).
Vitamin B12 (cobalamins: cyanocobalamin, hydroxocobalamin, methylcobalamin, hydroxocobalamin)	homocysteine; neuronal activity	Vitamin B12 acts as a coenzyme in metabolism of amino acids and fatty acids required for the synthesis of nucleic acids, erythrocytes, and in the maintenance of myelin (Pawlak 2014). Lower vitamin B12 status has been associated with increased rates of cognitive decline and dementia (Clarke 2007b; O'Leary 2012).
Pantothenic Acid (Vitamin B5)	energy; metabolism	Pantothenic acid (PA) is a component of coenzyme A, an essential cofactor in fatty acid oxidation, lipid elongation, and fatty acid synthesis (Kelly 2011). This may have an indirect effect in cognition.
Biotin (Vitamin H)	energy; metabolism	Biotin is also known as Vitamin H and is part of the B complex group of vitamins. They act as cofactors in carboxylase enzymes, fatty acid, and amino acid metabolism. This may have an indirect effect in cognition.
Vitamin C	antioxidant	Vitamin C has antioxidant functions and is required for the synthesis of noradrenaline from dopamine. It has been reported that Vitamin C levels have been lower than controls in patients with senile dementia of Alzheimer’s type (Jeandel 1989). In a longitudinal and cross‐sectional study it was found that higher vitamin C levels were associated with better memory performance (Perrig 1997).
Minerals
Calcium	neuronal activity	Calcium ions regulate a number of physiological processes including neuronal gene expression and the neuronal secretion of neurotransmitters (Delage 2014; Dolphin 2012). Supplementation with calcium together with vitamin D was found to have no significant association with incident cognitive impairment (Rossom 2012). Ozawa 2012 concluded that, in the general Japanese population, higher self‐reported dietary intakes of potassium, calcium, and magnesium reduced the risk of all‐cause dementia, especially Vascular Dementia (VaD). The proposed mechanism was through the reduction of of vascular risk factors.
Chromium	energy production; metabolism.	Chromium is needed for energy production and has been found to promote the effect of insulin involved in metabolism and storage of protein, carbohydrates and lipids within the CNS (Anderson 1997; Institute of Medicine 2011; Ozawa 2012). Chromium is involved in metabolism of nucleic acid, which is needed to build DNA, the genetic material in cells; and promotes synthesis of cholesterol and fatty acids needed for brain function. It may lower LDL cholesterol and triglyceride levels, raise HDL cholesterol levels and reduce high blood pressure (Preuss 1997), hence may affect vascular risk factors. Insulin resistance is implicated in the pathophysiological changes associated with Alzheimer's disease, and pharmaceutical treatments that overcome insulin resistance improve memory function in subjects with mild cognitive impairment (MCI) and early Alzheimer's disease. Chromium (Cr) supplementation improves glucose disposal in patients with insulin resistance and diabetes. A double‐blind RCT suggested that supplementation with Chromium picolinate can enhance cognitive inhibitory control and cerebral function in older adults at risk for neurodegeneration (Krikorian 2010). An additional study reported a positive correlation between cognitive function and serum chromium levels (Smorgon 2004).
Copper	antioxidant	Copper is a component of an antioxidant enzyme called superoxide dismutase that protects cells from damage by harmful free radicals. Copper is necessary for a healthy nerve system and taste sensitivity (Institute of Medicine 2011). Copper may promote non‐amyloidogenic processing of amyloid precursor protein (APP) and thereby lower the Aβ production in cell culture systems, and it increases lifetime and decreases soluble amyloid production in APP transgenic mice (Borchardt 1999). In Alzheimer patients, a decline of Aβ levels in CSF is reported in adults in the treatment group (Kaden 2011).
Iodine	neuronal development and structure.	Iodine is needed for the synthesis of thyroid hormones which, in turn, are needed for the myelination of the central nervous system. Iodine is necessary for the normal development of the brain. A deficiency of this mineral during critical periods of development in gestation can lead to intellectual disability and neurodevelopmental problems (Bath 2013a). Positive association was found between maternal iodine status and child IQ at age 8 years and reading ability at age 9 years (Bath 2013b).
Iron	neuronal activity	Iron is needed for development of oligodendrocytes and numerous enzymes that synthesise neurotransmitters such as noradrenaline, serotonin, and dopamine. It is important for production of the haemoglobin in red blood cells (Delage 2014; Institute of Medicine 2011). Regression analysis showed that non‐anaemic iron‐deficient adolescent girls who received iron performed better on a test of verbal learning and memory than girls in the control group (Bruner 1996)
Magnesium	energy, metabolism	Magnesium is involved in hundreds of enzyme reactions, including protein synthesis. It plays a role in energy production; can improve insulin sensitivity in diabetics; helps regulate blood sugar level; and regulates neuro‐muscular transmission. Higher self‐reported dietary intakes of potassium, calcium, and magnesium have been reported to reduce the risk of all‐cause dementia, especially VaD, in the general Japanese population (Ozawa 2012).
Manganese	metabolism	Manganese is needed to synthesise fatty acids and cholesterol, and metabolise carbohydrates and proteins. It is important for energy production. It promotes utilisation of other key nutrients like vitamin B1 (thiamine), biotin, choline, ascorbic acid, and vitamin E (Delage 2014). Manganese is needed for glucose metabolism, which helps regulate blood glucose. It is needed to make manganese superoxide dismutase (MnSOD), one of the key antioxidants that protects cells from free radical damage, and so helps maintains healthy nerves. It works synergistically with the B‐complex vitamins to generate an overall feeling of well‐being (Institute of Medicine 2011).
Molybdenum	metabolism	Molybdenum promotes normal cell function; and functions as a cofactor for three essential enzymes that play a vital role in carbohydrate metabolism, utilisation of iron, sulphite detoxification, and uric acid formation (Delage 2014; Institute of Medicine 2011).
Phosphorus	metabolism, neuronal structure and function.	Phosphorus is needed for metabolism of carbohydrates and fats to produce energy and is involved in the production of ATP required for growth and repair of cells and tissues; it is needed to make cell membranes. It helps the body utilise the B‐complex vitamins that support proper muscle and nerve function (Delage 2014; Institute of Medicine 2011).
Potassium	nerve transmission.	Potassium is involved in regulating nerve transmissions and muscle contractions. It helps the body handle sodium and so reduces the risk of high blood pressure (Berr 2012). It has been found to lower the risk of stroke and ischaemic heart disease. Potassium is needed for synthesis of protein from amino acids (Delage 2014; Institute of Medicine 2011). Higher self‐reported dietary intakes of potassium, calcium, and magnesium reduce the risk of all‐cause dementia, especially VaD, in the general Japanese population (Ozawa 2012).
Selenium	antioxidant.	Selenium is an important antioxidant especially in combination with vitamin E, in the central nervous system and other body tissues (Delage 2014; Mehdi 2013; Rahman 2007). Low selenium levels were found to be associated with poorer cognitive function (Berr 2012; Smorgon 2004). Supplementation with selenium has been associated with improved overall health, reducing oxidative stress and reducing the risk of dementia (Mehdi 2013).
Sodium	neuronal activity	Sodium is essential for regulating muscle contractions, nerve transmissions essential for normal CNS physiological mechanisms and homeostasis (Delage 2014; Institute of Medicine 2011).
Zinc	antioxidant neuronal activity	Zinc is a constituent of the antioxidant enzyme superoxide dismutase that helps reduce the harm from free radicals. Zinc regulates cell division and synthesis of genetic cell DNA. It is essential for reproduction, repair, and normal growth within the CNS (Delage 2014). Zinc is found in high levels in the brain where it performs catalytic, structural and regulatory roles in cellular metabolism. Zinc is bound to proteins but free zinc is present in synaptic vesicles and performs a role in neurotransmission mediated by glutamate and gamma‐aminobutyric acid (GABA). Short‐term deficits of zinc have been shown to impair certain measures of mental and neurological function while long‐term deficits of zinc, especially during gestation, result in malformation or deficits in attention, learning, memory and neuropsychological behaviour (Institute of Medicine 2011). Zinc was found to be capable of reducing post‐ischaemic injury to a variety of tissues and organs through a mechanism that might involve the antagonism of copper reactivity. Although the evidence for the antioxidant properties of zinc is compelling, the mechanisms are still unclear (Powell 2000).
* Only orally‐administered supplements taken at any dose for at least 12 weeks are considered. Supplements that combine vitamins or minerals are eligible as well. Footnotes Aβ: Amyloid β Protein AD: Alzheimers' Disease APP: amyloid precursor protein ATP: Adenosine triphosphate CNS: central nervous system Cr: Chromium CSF: CerebroSpinal Fluid DNA: DeoxyriboNucleic Acid GABA: Gamma‐AminoButyric Acid HDL: high‐density lipoproteins IQ: Intelligence quotient LDL: Low‐density lipoprotein MCI: Mild Cognitive Impairment MnSOD: manganese superoxide dismutase PLP: Pyridoxal 5' phosphate PMP: pyridoxamine 5' phosphate PNP: Pyridoxine 5'‐phosphate VaD: Vascular Dementia VDR: Vitamin D receptor 25(OH)D: serum hydroxyvitamin D