Introduction
Alzheimer’s Disease (AD) was first described by Alois Alzheimer in 1907. He described this condition in a 51-year-old female who presented with symptoms of psychiatric disturbance along with swift deterioration of memory [1]. Decades later, it is now recognized that AD is one of the major causes of dementia in population under 65 years, other causes being dementia with Lewy Body Dementia (LBD), Frontotemporal Dementia (FTD), Vascular Dementia (VaD) and alcohol associated dementia [2]. AD represents a major public health problem and in United States alone, a person develops AD every 68 seconds and Americans spend more than $200 billion annually on Alzheimer’s related expenses [3]. Results of population based studies have shown that risk factors associated with the development of AD include increasing age, certain genetic factors (e.g., presence of apolipoprotein E epsilon 4 allele), fewer years of education and head trauma [4].
AD dementia must be differentiated from other causes of dementia like LBD, FTD and VaD [5]. Moreover, due to the variability of the brain regions affected, AD can present with dysfunction of different domains like vision, sensory-motor functions, judgment and personality [6]. In order to distinguish AD from other causes of dementia, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) has put forth the clinical criteria for establishing a diagnosis of AD. According to this criterion, AD is characterized by: (I) Progressive decline in cognitive functions, which may include impairment of memory, or (Ia) Loss of ability to comprehend words and verbal commands (aphasia); (Ib) Inability to complete tasks involving coordination of muscles (apraxia); (Ic) Inability to recognize and make use of familiar objects (agnosia); (Id) Inability to plan, organize and execute routine activities; (II) All indications mentioned above under ‘I’ getting worse with the passage of time; (III) All other causes of dementia and cognitive decline are excluded [6,7].
The first ever reported histopathological features of AD include the presence of extracellular amyloid plaques and intracellular Neurofibrillary Tangles (NFT). But recently, newer histopathological features have been identified. These features include degeneration of neuronal synapses, loss of neurons in the hippocampus and aneuploidy. However, current histopathological criteria for establishment of AD still take into account of only the presence of extracellular amyloid plaques and intracellular NFT [8]. Among the most accepted hypotheses that try to explain the pathogenesis of AD is the Aβ cascade hypothesis. Previously, mutation in beta-Amyloid Precursor Protein (APP), which is implicated in the normal function of neurons and cerebral development, has been speculated as the basic cause of accumulation of Aβ proteins and the pathogenesis of AD [9]. Later, mutations in other genes like presenilin 1 and presenilin 2 were also discovered to be involved in the generation of Aβ pools [10]. But how Aβ aggregation contributes in the pathophysiology of AD largely remains unclear. Previously the intercellular Aβ plaques were thought to be toxic for cells. But recent data has suggested the role of intracellular Aβ proteins, which actually don’t get sequestered into the extracellular plaques, as the toxic triggers dictating the progression of AD [11]. Also, it has been recently shown that intracellular accumulation of Aβ proteins precedes the formation of extracellular Aβ proteins plaques and NFT formation [12]. The role of intracellular Aβ protein in the progression of AD is backed by recent experiments on transgenic mice that have shown that increased deposits of Aβ proteins within the cells are associated with accelerated cell death [13].
Another important culprit in the development of AD is oxidative stress and ROS [14]. Several factors make brain particularly vulnerable to the damage caused by oxidative stress. These factors include relatively lower levels of antioxidants in the brain, higher levels of polyunsaturated fatty acids in the brain (these fatty acids rapidly fall prey to ROS), presence of metallic ions in the brain and higher oxygen utilization by this organ [15]. Increased oxidative stress causes damage to the constituents of cells like carbohydrates, lipids, proteins, RNA, DNA [16]. Indirect mechanisms can exacerbate the damage caused by direct effects of oxidative stress. Oxidative stress accentuates the expression of Inducible Nitric Oxide Synthase (iNOS) and potentiates the action of neuronal NOS (nNOS). This increases the production of nitric oxide (NO), which can then interact with superoxide anions to form peroxynitrite anions. Peroxynitrite anions are short lived, highly reactive molecules that can interact and damage a variety of structures in the cellular environment, especially with the compounds containing sulfhydryl groups [17].
Oxidative stress alters the protein structure and altered protein structure in turn further accelerates oxidative stress. It seems both these processes are interrelated. ROS induce protein oxidation, thereby modifying protein structure and causing their dimerization and aggregation [18]. These structurally and functionally abnormal proteins get accumulated in the form of cytoplasmic inclusions and are seen in the form of NFT (tau aggregates) and Aβ plaques [19]. On the other hand, Aβ plaques can also lead to the increased production of ROS. Aβ (1-42) is the more abundant and more toxic species of Aβ proteins seen in AD [20]. Aβ (1-42) peptides possess a residue of methionine at the position 35, which is thought to be responsible for the toxicity of Aβ (1-42) peptides [21]. Oxidation of methionine leads to the formation of methionine sulfoxide, which can undergo irreversible oxidation to form methionine sulfone [22]. Methionine sulfoxide reductase can guide the enzymatic reduction of methionine sulfoxide back into methionine [23]. Furthermore, activity of methionine sulfoxide reductase is also found to be impaired in AD [24]. Methionine peroxide plays a pivotal role in the toxicity and oxidative stress caused by Aβ (1-42) peptides. The lone-pair of electrons on the S atom of methionine undergoes one atom oxidation and as a result sulfuranyl radicals (MetS.+) are generated [21,25]. Sulfuranyl radicals can trigger the generation of other ROS like superoxides and sulfoxides by interacting with molecular oxygen [26].
Another important factor that greatly aggravates the severity of oxidative stress in AD is the relative absence or decreased function of different antioxidant mechanisms of the body. Glutathione is a major antioxidant that confers protection to the brain tissues by causing detoxification of damaging ROS [27]. One of the basic reasons of oxidative stress build-up in AD is the decreased levels of glutathione in the brain [28]. Other important members of cellular antioxidant mechanism include Superoxide Dismutase (SOD) and Catalase (CAT). SOD is the antioxidant responsible for converting toxic superoxide ions into less toxic hydrogen peroxide [29]. CAT takes this reaction one step further and turns hydrogen peroxide into water [30]. Investigations showed that the levels of SOD and CAT were declined in patients with AD [31]. Gluthathione peroxidase (GPx) and glutathione reductase (GR) represent other important constituents of the cellular defence mechanism against oxidative stress. GPx is responsible for the metabolism of lipid hydroperoxides and hydrogen peroxide [32] and GR governs the reaction that helps in the regeneration of Gluthathione (GSH) [33]. In nutshell, both increase in the oxidative stress and decrease in the cellular defence mechanism against ROS contribute in the pathogenesis of AD.
As mentioned earlier, AD has got a large global burden and the treatment process is very expensive. Therefore, it is the need of the hour to come-up with novel therapeutic strategies for the treatment of AD that are proficient and cost-effective at the same time. One such method is the supplementation of diet with antioxidant vitamins. So, the basic purpose of this review article is to take into account the current literature regarding the use of vitamin supplementation as an adjuvant treatment of AD and determine the efficacy of this treatment strategy.
Discussion
Recently, there has been build-up of interest in exploring novel approaches for the treatment of AD. Dietary modification is one such approach that has shown to influence the development, progression and treatment of AD. Use of antioxidants has shown significant promise in decreasing oxidative stress, inflammation and neuronal loss in neurodegenerative disorders. Vitamins are potent antioxidants and therefore can be used as an adjuvant therapy for the treatment of AD.
Vitamin A and Beta-Carotenes
Results of some studies have found that serum plasma and Cerebrospinal Fluid (CSF) levels of vitamin A and beta carotenes were significantly low in AD patients when compared to controls [34]. Vitamin A and beta carotene have shown to influence multiple aspects of neurodegenerative disorders. Vitamin A plays an important role in neuron development in early life and remains active in adult nervous system. Moreover, this vitamin has shown to protect and assist in regeneration of neurons during neurodegeneration [35]. Another effect of vitamin A and beta carotenes is that they inhibit the formation and promote the destabilization of Aβ fibrils [35]. Furthermore, oligomerization of Aβ fibrils is an important mechanism contributing to neuronal toxicity in AD. Vitamin A has shown to decrease the aggregation and oligomerization of Aβ40 and Aβ42 fibrils [36]. Vitamin A and beta carotene have also been found to decrease the decline of cognition in AD. In addition, higher level of these vitamins has also been associated with better memory performance and spatial learning in such patients [34–36].
B Vitamins
Among B vitamins, pyridoxine (B6), folic acid (B9), and cobalamin (B12) have shown to have potential in managing symptoms of AD. Hyperhomocysteinaemia is an independent and important risk-factor for a number of diseases including AD [37]. Homocysteine is responsible for increasing toxicity for neurons in a number of ways. One such way, is by its ability to trigger the generation of ROS and increase the oxidative stress [38]. Vitamin B6, B9 and B12 have shown to decrease the level of homocysteine, thereby helping in the control of this modifiable risk-factor for AD [39].
Low levels of vitamin B6 have been implicated in the pathogenesis of AD. Study of patients with AD showed that white matter lesions were common in the patients having low serum pyridoxine levels [40]. Cu (II) complexes of Aβ peptides represent an important trigger of metal centered oxidative stress in AD. Pyridoxine has shown to inhibit this mechanism of oxidative stress [41]. The results of a randomized, double blinded trial on 89 patients with AD showed that the use of multivitamin supplements (including vitamin B6, B9 and B12) is an excellent adjuvant when used in combination with usual therapy for AD (p = 0.008) [39]. Another study proved the same point where multivitamin supplementations was found to decrease the levels of homocysteine in treatment group as compared to placebo group (p <0.001) [42].
Low level of serum folate is another predictor for AD. A study inducting 816 individuals showed that there is a statistically significant (p=0.014) relationship between decreased serum level of folate and AD [43]. The role, folate plays in AD is perhaps due to its ability to mitigate the serum level of homocysteine and resultant oxidative stress caused by it [44]. Moreover, inadequate supply of folate has also been linked with significant shrinkage of cerebral cortex [45]. In addition, reduced plasma levels of folate has also been linked with the induction of other mechanisms of AD pathogenesis including increased calcium influx into the cells leading to subsequent apoptosis, accumulation of NFT and aggregations of Aβ peptides [46]. A 10-year-study was performed to find the relation between dietary habits and relative risk of developing AD. The study included 579 individuals and a follow-up was performed after 9.3 years. During that time 57 participants developed AD. Result of the study showed that increased intake of folate was associated with significantly decreased risks for developing AD [47]. Another study included 965 patients without dementia and follow-up was performed after a period of almost 6 years. The result of the study confirmed a statistically significant relation (p= 0.02) between higher folate intake and lower incidence of AD [48].
The plasma levels of vitamin B12 were also found to be deficient in cases of AD [49]. It is also an established fact that deficiency of vitamin B12 exacerbates several aspects of AD including cognitive decline and dementia in patients with AD. Dementia and cognitive decline were quite prominent in AD patients with subnormal vitamin B12 levels as compared to patients with normal plasma levels of B12 vitamin [50]. Elevated plasma level of homocysteine is an important risk factor for gray matter atrophy. Using high dose of B vitamins, including 0.8mg B9, 20mg B6 and 0.5mg B12, over a period of 2 years has been demonstrated to decrease homocysteine induced gray matter atrophy [51]. Therefore, vitamin B12 supplementation can be used as an excellent adjuvant for the treatment of cognitive decline associated with age or neurodegenerative diseases including AD [52].
Vitamin C
Like other antioxidant vitamins, the plasma levels of vitamin C were found to be significantly lower in patients with AD despite adequate intake of this vitamin in the diet [53]. This again proves the fact that oxidative stress induces damage in AD and antioxidant vitamins offer certain degree of protection against this stress. Vitamin C alters the progression of AD by interfering with different aspects of AD pathology. Results of numerous invitro and invivo studies have shown that vitamin C can decrease oxidative stress. Vitamin C can hinder the structural progression of AD by preventing the oligomerization of Aβ peptides [54]. Brain injury induces oxidative stress and decreases the level of antioxidants like vitamin C and SOD. Supplementation with vitamin C improves the level of SOD, which in turn helps in lowering the oxidative stress and resultant brain injury [55].
Some studies have suggested that normal intake of vitamin C; even without additional supplementation can have neuroprotective effects in patients with AD. Adequate vitamin C intake can decrease cognitive decline in AD patients [56]. Results from a prospective observational study (n=4740) suggested that additional supplementation with antioxidant vitamins like vitamin C and E over a time period of 3 years was associated with both decreased incidence and prevalence of AD [57].
Vitamin D
The analysis of current literature on the relationship between vitamin D deficiency and AD revealed a direct relation between decreased serum level of vitamin D and AD. Vitamin D levels are found to be significantly lower in patients with AD as compared to normal controls [58]. Until recently, the role of vitamin D deficiency in the progression of AD was unknown. But genetic studies have been able to explain this relation in more detail. Results of genetic studies found a very strong relationship (p<0.001) between over-expression of vitamin D receptors (VDR) or vitamin D supplementation with the suppression of APP transcription [59]. Another mechanism through which vitamin D deficiency cause brain injury is via enhanced inflammation due to different types of VDR polymorphisms [60]. Vitamin D depletion has also been linked to brain atrophy [61]. The role of vitamin D in the pathogenesis of AD does not end here. Vitamin D somehow also helps in the clearance of Aβ plaques, a distinct feature of AD and low levels of vitamin D have also been linked with increased incidence of cognitive decline [62].
There have been encouraging results regarding the adjuvant supplementation of vitamin D as a treatment protocol for AD. The results from a large population based study, which was conducted on 5,596 women (age around 80 years), showed that women who were deficient in vitamin D intake scored less on Short Portable Mental State Questionnaire (SPMSQ) as compared to females with adequate vitamin D intake (p<0.001) [63]. Memantine is considered as one of the first line drugs for the treatment of mild to moderate AD [64]. Result of a study conducted on 43 AD patients showed that use of vitamin D as an adjuvant supplement in addition to memantine treatment is far superior to the use of memantine monotherapy (p< 0.001) [65].
Vitamin E
Vitamin E represents a group of 8 antioxidants (containing 4 tocotrienols and 4 tocopherols). It has been reported that decreased levels of plasma vitamin E is associated with increased risk of neurodegenerative disorders like AD and Mild Cognitive Impairment (MCI). Moreover, the level of vitamin E damage products (5-nitro-γ-tocopherol etc.) increases significantly in AD and MCI [66]. Vitamin E deficiency can lead to destruction of neurons and has been implied in the cases of cerebellar atrophy [67]. Vitamin E acts as potent antioxidant which can slow down the progression of AD at multiple levels. Increased oxidative stress induced by Aβ plaques is a known risk-factor for the neuronal death and resultant brain injury in AD. Vitamin E acts as a scavenger for these free radicals and provides certain degree of neuroprotection [68]. Vitamin E also offers protection against AD via some alternate methods. For instance, glutamate-induced neuronal cell death is the result of inflammation caused by 12-lipoxygenase pathway. Vitamin E can inhibit this inflammation induced neuronal death [69]. Moreover, consumption of vitamin E has also been linked with the regeneration of SOD, which undergoes decline in AD [55]. Among the different forms of vitamin E, α-tocopherols and γ-tocopherols provide greatest degree of protection against AD and cognitive decline [70].
A population based cohort study included 5395 individuals to evaluate the efficacy of dietary supplementation with antioxidants to provide protection against AD. Results showed that among all the antioxidant used, vitamin E provided significant degree of protection (p = .02) against dementia and AD [71]. Moreover, use of multivitamin supplements containing 30 International Units (IU) of alpha tocopherols can act as beneficial adjuvant for the treatment of several neurodegenerative disorders like AD and Parkinson’s disease [72].
Vitamin K
There have been some studies that link the deficiency of vitamin K to AD [73]. The exact role of vitamin K still needs to be described. But it is believed that the protection offered by vitamin K in AD is due to its ability to reduce oxidative stress. This fact is backed by findings that vitamin K can prevent oxidative stress induced cell death following the activation of 2-lipoxygenase pathway [74]. Moreover, higher serum phylloquinone concentration is also linked with improved cognitive functions [75].
There is a lack of clinical trials on humans that could explain the relationship between vitamin K supplementation and improvement in AD. However, results of animal experimentation has shown that supplementation of diet with vitamin K can decrease the degradation of neurons and decline of cognitive functions [76].
Conclusion
Alzheimer’s disease represents one of the most important age related neurodegenerative disorders. Oxidative stress represents one of the most important mechanism involved in the development and progression of this condition. Use of antioxidants is a novel approach that can help treat this condition. The use of several antioxidant vitamins as an adjuvant treatment for AD has always been underestimated. There is a need for more clinical research to study their potential, such that it can be incorporated into clinical practice to speed-up the recovery of patients suffering from this disorder.
Authors’ Contributions
ABB conducted the literature search, complied data and wrote the manuscript. MU assisted ABB and performed the revision. Both authors approved the final version.
[1]. Alzheimer A, Uber eine eigenartige Erkrankung der Hirnrinde Allgemeine Zeits Psychiat Psychisch Gerichtlich Med 1907 64:146-48. [Google Scholar]
[2]. Harvey RJ, Skelton-Robinson M, Rossor MN, The prevalence and causes of dementia in people under the age of 65 years J Neurol Neurosurg Psychiatry 2003 74:1206-09. [Google Scholar]
[3]. Alzheimer’s Association2012 Alzheimer’s disease facts and figures Alzheimers Dement 2012 8:131-68. [Google Scholar]
[4]. Lindsay J, Laurin D, Verreault R, Hébert R, Helliwell B, Hill GB, Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian study of health and aging Am J Epidemiol 2002 156:445-53. [Google Scholar]
[5]. Karantzoulis S, Galvin JE, Distinguishing Alzheimer’s disease from other major forms of dementia Expert Rev Neurother 2011 11:1579-91. [Google Scholar]
[6]. Castellani RJ, Rolston RK, Smith MA, Alzheimer Disease Dis Mon 2010 56:484-546. [Google Scholar]
[7]. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimers Dement 2011 7:263-69. [Google Scholar]
[8]. Swerdlow RH, Pathogenesis of Alzheimer’s disease Clin Interv Aging 2007 2:347-59. [Google Scholar]
[9]. Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, Beta-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity Cell 1995 81:525-31. [Google Scholar]
[10]. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Candidate gene for the chromosome 1 familial Alzheimer’s disease locus Science 1995 269:973-77. [Google Scholar]
[11]. Lesne S, Kotilinek L, Amyloid plaques and amyloid-beta oligomers: An ongoing debate J Neurosci 2005 25:9319-20. [Google Scholar]
[12]. Gouras GK, Tsai J, Naslund J, Vincent B, Vincent B, Edgar M, Intraneuronal Abeta42 accumulation in human brain Am J Pathol 2000 156:15-20. [Google Scholar]
[13]. Bayer TA, Wirths O, Intracelluar accumulation of amylois beta- A predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease Front Aging Neurosci 2010 2:8 [Google Scholar]
[14]. Butterfield DA, Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review Free Radic Res 2002 36:1307-13. [Google Scholar]
[15]. Butterfield DA, Castegna A, Lauderback CM, Drake J, Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death Neurobiol Aging 2002 23:655-64. [Google Scholar]
[16]. Butterfield DA, Reed T, Newman SF, Sultana R, Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment Free Radic Biol Med 2007 43:658-77. [Google Scholar]
[17]. Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS, Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide Chem Res Toxicol 1992 5:834-42. [Google Scholar]
[18]. Hensley K, Hall N, Subramaniam R, Cole P, Harris M, Aksenov M, Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation J Neurochem 1995 65:2146-56. [Google Scholar]
[19]. Butterfield DA, Kanski J, Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins Mech Ageing Dev 2001 122:945-62. [Google Scholar]
[20]. Selkoe DJ, Alzheimer’s disease: genes, proteins, and therapy Physiol Rev 2001 81:741-66. [Google Scholar]
[21]. Butterfield DA, Boyd-Kimball D, The critical role of methionine 35 in Alzheimer’s amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity Biochim Biophys Acta 2005 1703:149-56. [Google Scholar]
[22]. Moskovitz J, Berlett BS, Poston JM, Stadtman ER, Methionine sulfoxidereductase in antioxidant defence Methods Enzymol 1999 300:239-44. [Google Scholar]
[23]. Maher P, Redox control of neural function: background, mechanisms, and significance Antioxid Redox Signal 2006 8:1941-70. [Google Scholar]
[24]. Gabbita SP, Aksenov MY, Lovell MA, Markesbery WR, Decrease in peptide methionine sulfoxidereductase in Alzheimer’s disease brain J Neurochem 1999 73:1660-66. [Google Scholar]
[25]. Pogocki D, Schoneich C, Redox properties of Met(35) in neurotoxic beta-amyloid peptide. A molecular modeling study Chem Res Toxicol 2002 15:408-18. [Google Scholar]
[26]. Milller B, Williams T, Schoneich C, Mechanism of sulfoxide formation through reaction of sulfur radical cation complexes with superoxide of hydroxide ion in oxygenated aqueous solution J Am Chem Soc 1996 118:11014-25. [Google Scholar]
[27]. Dringen R, Gutterer JM, Hirrlinger J, Glutathione metabolism in brain: metabolic interaction between astrocytes and neurons in the defence against reactive oxygen species Eur J Biochem 2000 267:4912-16. [Google Scholar]
[28]. Saharan S, Mandal PK, The emerging role of glutathione in Alzheimer’s disease J Alzheimers Dis 2014 40:519-29. [Google Scholar]
[29]. Zelko IN, Mariani TJ, Folz RJ, Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression Free Radical Biol and Medi 2002 33:337-49. [Google Scholar]
[30]. Chelikani P, Fita I, Loewen PC, Diversity of structures and properties among catalases Cell Mol Life Sci 2004 61:192-208. [Google Scholar]
[31]. Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease Exp Neurol 1998 150:40-44. [Google Scholar]
[32]. Arthur JR, The glutathione peroxidases Cell Mol Life Sci 2000 57:1825-35. [Google Scholar]
[33]. Shigeoka S, Onishi T, Nakano Y, Kitaoka S, Characterisation and physiological function of glutathione reductase in Euglena gracilis z Biochem J 1987 242:511-15. [Google Scholar]
[34]. Bourdel-Marchasson I, Delmas-Beauviex M-C, Peuchant E, Richard-Harston S, Decamps A, Reignier B, Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients Age and Ageing 2001 30:235-41. [Google Scholar]
[35]. Ono K, Yamada M, Vitamin A and Alzheimer’s disease Geriatrics Gerontol Intl 2012 12:180-88. [Google Scholar]
[36]. Takasaki J, Ono K, Yoshiike Y, Ikeda T, Morinaga A, Takashima A, Vitamin A has anti-oligomerization effects on amyloid-β in vitro J Alzheimer’s Dis 2011 27:271-80. [Google Scholar]
[37]. Morris MS, Homocysteine and Alzheimer’s disease Lancet Neurol 2003 2(7):425-28. [Google Scholar]
[38]. Gröber U, Kisters K, Schmidt J, Neuroenhancement with vitamin B12—Underestimated neurological significance Nutrients 2013 5:5031-45. [Google Scholar]
[39]. Sun Y, Lu CJ, Chien KL, Chen ST, Chen RC, Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer’s disease: A 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients Clin Ther 2007 29:2204-14. [Google Scholar]
[40]. Mulder C, Scheltens P, Barkhof F, Gundy C, Verstraeten RA, de Leeuw FE, Low vitamin B6 levels are associated with white matter lesions in Alzheimer’s disease J Am Geriatr Soc 2005 53:1073-74. [Google Scholar]
[41]. Hashim A, Wanga L, Junej K, Ye Y, Zhao Y, Ming LJ, Vitamin B6s inhibit oxidative stress caused by Alzheimer’s disease-related cu(II)-β-amyloid complexes-cooperative action of phospho-moiety Bioorg MedChem Lett 2011 21:6430-32. [Google Scholar]
[42]. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial J Am Med Ass 2008 300:1774-83. [Google Scholar]
[43]. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Homocysteine and folate as risk factors for dementia and Alzheimer disease Am J of Clin Nutr 2005 82:636-43. [Google Scholar]
[44]. Tchantchou F, Shea TB, Folate deprivation, the methionine cycle, and Alzheimer’s disease Vitam Horm 2008 79:83-97. [Google Scholar]
[45]. Snowdon DA, Tully CL, Smith CD, Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study Am J Clin Nutr 2000 71(4):993-98. [Google Scholar]
[46]. Hinterberger M, Fischer P, Folate and Alzheimer: when time matters J Neural Transm 2013 120:211-24. [Google Scholar]
[47]. Corrada MM, Kawas CH, Hallfrisch J, Muller D, Brookmeyer R, Reduced risk of Alzheimer’s disease with high folate intake: the Baltimore longitudinal study of aging Alzheimer’s and dementia 2005 1:11-18. [Google Scholar]
[48]. Luchsinger JA, Tang M-X, Miller J, Green R, Mayeux R, Relation of higher folate intake to lower risk of Alzheimer disease in the elderly Arch Neurol 2007 64:86-92. [Google Scholar]
[49]. Politis A, Olgiati P, Malitas P, Albani D, Signorini A, Polito L, Vitamin B12 levels in Alzheimer’s disease: association with clinical features and cytokine production J Alzheimers Dis 2010 19:481-88. [Google Scholar]
[50]. Meins W, Müller-Thomsen T, Meier-Baumgartner HP, Subnormal serum vitamin B12 and behavioural and psychological symptoms in Alzheimer’s disease Int J Geriatr Psychiatry 2000 15:415-18. [Google Scholar]
[51]. Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment Proc Natl Acad Sci U S A 2013 110:9523-28. [Google Scholar]
[52]. Gröber U, Kisters K, Schmidt J, Neuroenhancement with Vitamin B12—Underestimated neurological significance Nutrients 2013 5:5031-45. [Google Scholar]
[53]. Rivière S, Birlouez-Aragon I, Nourhashémi F, Vellas B, Low plasma vitamin C in Alzheimer patients despite an adequate diet Int J Geriatr Psychiatry 1998 13:749-54. [Google Scholar]
[54]. Montilla-López P, Muoz-Águeda MC, FeijóoLópez M, Muñoz-Castañeda JR, Bujalance-Arenas I, Túnez-Fiñana I, Comparison of melatonin versus vitamin C on oxidative stress and antioxidant enzyme activity in Alzheimer’s disease induced by okadaic acid in neuroblastoma cells Eur J of Pharmacol 2002 451:237-43. [Google Scholar]
[55]. Ishaq GM, Saidu Y, Bilbis LS, Muhammad SA, Jinjir N, Shehu BB, Effects of α-tocopherol and ascorbic acid in the severity and management of traumatic brain injury in albino rats J Neurosci Rural Pract 2013 4:292-97. [Google Scholar]
[56]. Harrison FH, A critical review of Vitamin C for the prevention of age-related cognitive decline and Alzheimer’s disease J Alzheimers Dis 2012 29:711-26. [Google Scholar]
[57]. Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study Arch Neurol 2004 61:82-88. [Google Scholar]
[58]. Annweiler C, Llewellyn DJ, Beauchet O, Low serum vitamin D concentrations in Alzheimer’s disease: a systematic review and meta-analysis J Alzheimers Dis 2013 33:659-74. [Google Scholar]
[59]. Wang L, Hara K, Van Baaren JM, Price JC, Beecham GW, Gallins PJ, Vitamin D receptor and Alzheimer’s disease: a genetic and functional study Neurobiol Aging 2012 33:1844 [Google Scholar]
[60]. Lehmann DJ, Refsum H, Warden DR, Medway C, Wilcock GK, Smith AD, The vitamin D receptor gene is associated with Alzheimer’s disease Neurosci Lett 2011 504:79-82. [Google Scholar]
[61]. Annweiler C, Annweiler T, Montero-Odasso M, Bartha R, Beauchet O, Vitamin D and brain volumetric changes: Systematic review and meta-analysis Maturitas 2014 78:30-39. [Google Scholar]
[62]. Soni M, Kos K, Lang IA, Jones K, Melzer D, Llewellyn DJ, Vitamin D and cognitive function Scand J Clin Lab Invest Suppl 2012 243:79-82. [Google Scholar]
[63]. Annweiler C, Schott AM, Rolland Y, Blain H, Herrmann FR, Beauchet O, Dietary intake of vitamin D and cognition in older women: a large population-based study Neurology 2010 75:1810-16. [Google Scholar]
[64]. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ, Memantine in moderate-to-severe Alzheimer’s disease N Engl J Med 2003 348:1333-41. [Google Scholar]
[65]. Annweiler C, Herrmann FR, Fantino B, Brugg B, Beauchet O, Effectiveness of the combination of memantine plus vitamin D on cognition in patients with Alzheimer disease: a pre-post pilot study Cogn Behav Neurol 2012 25:121-27. [Google Scholar]
[66]. Mangialasche F, Xu W, Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, Tocopherols and tocotrienols plasma levels are associated with cognitive impairment Neurobiol Aging 2012 33:2282-90. [Google Scholar]
[67]. Aoki K, Washimi Y, Fujimori N, Maruyama K, Maruyama K, Yanagisawa N, Familial idiopathic vitamin E deficiency associated with cerebellar atrophy Rinsho Shinkeigaku 1990 30:966-71. [Google Scholar]
[68]. Yatin SM, Varadarajan S, Butterfield DA, Vitamin E prevents Alzheimer’s amyloid β-peptide (1-42)-induced neuronal protein oxidation and reactive oxygen species production J Alzheimer’s Dis 2000 2:123-31. [Google Scholar]
[69]. Khanna S, Parinandi NL, Kotha SR, Roy S, Rick C, Bibus D, Nanomolar vitamin E α-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection J Neurochem 2010 112:1249-60. [Google Scholar]
[70]. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change Am J Clin Nutr 2005 81:508-14. [Google Scholar]
[71]. Devore EE, Grodstein F, van Rooij FJ, Hofman A, Stampfer MJ, Witteman JC, Dietary antioxidants and long-term risk of dementia Arch Neurol 2010 67:819-25. [Google Scholar]
[72]. Pham DQ, Plakogiannis R, Vitamin E supplementation in Alzheimer’s disease, Parkinson’s disease, tardive dyskinesia, and cataract: Part 2 Ann Pharmaco ther 2005 39:2065-72. [Google Scholar]
[73]. Allison AC, The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease Med Hypotheses 2001 57:151-55. [Google Scholar]
[74]. Li J, Wang H, Rosenberg PA, Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes J Neurosci Res 2009 87:1997-2005. [Google Scholar]
[75]. Presse N, Belleville S, Gaudreau P, Greenwood CE, Kergoat MJ, Morais JA, Vitamin K status and cognitive function in healthy older adults Neurobiol Aging 2013 34:2777-83. [Google Scholar]
[76]. Crivello NA, Casseus SL, Peterson JW, Smith DE, Booth SL, Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides J Nutr Biochem 2010 21:1083-88. [Google Scholar]