Analysis of the brain, serum and urine of persons with dementia and Alzheimer's disease has shown some significant differences between normal healthy individuals and those with developing cognitive impairment and Alzheimer's disease. Whilst these markers may not necessarily be definitive for diagnosis of Alzheimer's disease when viewed alone, they may be indicative of progression of the condition, and by understanding what changes in the levels of the markers means, they do suggest possible causes for the development of the symptomology associated with the condition. The explanations below are quite technical, but briefly deficiency of any one or all of vitamin B2, vitamin B12, iron, selenium, iodine or selenium could all cause the changes in metabolic markers outlined previously and as such contribute to the development of dementia.
Homocysteine: Elevated homocysteine levels in the serum of persons with dementia/AD has been suggested to result in vascular damage due to the formation of thiol-linked adjuncts between homocysteine (Hcy) and various proteins in the vascular wall. Whilst this may be possible, elevated homocysteine is also a surrogate marker of vitamin B12 deficiency, folate deficiency, vitamin B2 deficiency, iron deficiency and/or vitamin B6 deficiency. In addition, elevated homocysteine is indicative of reduced movement of dietary 5-methyl-tetrahydrofolate into the folate cycle and of methionine derived sulphur into the sulphation cycle. Lack of folate cycling, by virtue of reduced production of guanosine triphosphate (GTP) in turn would result in reduced production of tetrahydrobiopterin (BH4). Reduced levels of BH4 have been found in the serum of subjects with Senile Dementia of Alzheimer's disease (SDAD)(1) and in the cerebrospinal fluid (CSF) of SDAD at post-mortem (2,3) and in the temporal lobe of patients dying with SDAD (4). Synthesis of dopamine and noradrenalin is dependent upon the BH4 dependent enzyme tyrosine hydroxylase, whilst synthesis of serotonin is dependent upon the BH4 dependent enzyme tryptophan hydroxylase. Reduced brain dopamine, nor-adrenalin and serotonin levels have been found in subjects with dementia plus Lewy Bodies and in AD patients (5,6,7). Furthermore, there is evidence that serotonin responsive neurons may be decreased in AD (8). In addition, the reduced levels of BH4 would also result in reduced activity of the nitric oxide generating endothelial NOS leading to restricted blood flow in the brain of those with AD (9). Restricted activity of NOS has been postulated to enhance the smyloid (Aβ) pathology in AD (10,11,12), and to increase Alzheimer disease burden (13). Restricted NOS activity has also been implicated in poorer memory outcomes in AD (14,15), and in reduced levels of nitric oxide in the plasma of persons with AD (16).
Many studies have shown a correlation between homocysteine reduction in cognitive ability as judged by Mini Mental Score Estimation (MMSE)(17,18,19,20,21).
As stated above, reduced movement of methionine derived sulphur into the sulphation pathway occurs when there is reduced activity of the enzyme cystathionine beta synthase (CBS), a vitamin B6 and heme-dependent enzyme. Function of the enzyme is ultimately also dependent upon functional B2 activity as FAD is required for the formation of pyridoxal-5-phosphate and for the production of heme. Elevated homocysteine, thus, is also indicative of low CBS activity and would result in reduced production of cystathionine and reduced hydrogen sulphide (H2S) production and reduced formation of iron-sulphur (Fe-S) proteins such as aconitase. The reduced levels of H2S and the reduced activity of aconitase, both of which are found in AD, could therefore be a function of low iron, low vitamin B6 or lack of production of FAD from dietary vitamin B2.
Elevated homocysteine is also linked to low vitamin B12 levels, with homocysteine increasing as vitamin B12 reduces below 250 pmol/L. The question though is "Why does CBS not remove homocysteine as the levels rise?". The reason for this lies in the function of S-adenosyl methionine (SAM) in turning on CBS. Thus, as SAM levels increase, SAM binds to CBS and turns the enzyme on (22,23). As methyl B12 levels drop, the production of SAM drops and so CBS activity would also drop and homocysteine would rise.
Vitamin B12: The brain is "stocked" with vitamin B12 "in utero" and there-after tried to maintain functional B12 levels in the brain, however, over time it is known that these levels drop. We know of no study correlating the level of vitamin B12 in the brains at 20 years of age, correlates with the development of B12 deficiency in the brain in later years. Low plasma B12 levels have also been associated with low cognitive scores in AD (24). Low plasma B12 is also associated with accelerated brain shrinkage.
Apart from the obvious lack of dietary vitamin B12, vitamin B12 deficiency, as seen in AD could also result from low vitamin B2 intake and/or lack of production of FAD. The later would result in increased usage of vitamin B12, as is evidenced for the increased incidence of vitamin B12 deficiency in hypothyroidism (25,26). Reduced production of FAD, would lead to a reduced activity of the FAD-dependent enzyme methionine synthase reductase, which is the enzyme responsible for removing oxidized Co(II)B12 and producing methyl Co(III) B12 from Co(II) B12 plus S-Adenosyl Methionine. Lack of function of methionine synthase reductase results in a much higher consumption of vitamin B12 and an inability to use either hydoxocobalamin or cyanocobalamin provided as a supplement. Lack of methyl Co(III)B12, by virtue of its role in the methylation cycle, would also result in reduced production of phosphatidyl choline, produced by tri-methylation of phosphatidyl ethanolamine by phosphatidyl ethanolamine methyl transferase (PEMT). In addition reduced methylation would also result in reduced production of acetyl-choline and subsequent degeneration of cholinergic neurones, which is a feature of AD (27). In addition, lack of methylation due to low methyl B12 levels can explain the reduced activity of phosphatidylethanolamine-N-methyltransferase in the brains of persons with AD (28), with subsequent reduction in phosphatidyl-choline, choline and acetyl-choline. Vitamin B12 deficiency in turn leads to the incorporation of abnormal fatty acids into the myelin sheath and cerebrosides (29,30). This is postulated to result in increased rate of demyelination in the nervous system (31).
Further to this is the effect that reduced levels of SAM production observed in B12 deficiency, with the subsequent reduction in CBS activity (see above). This then reduces the flow of dietary sulphur from the methionine in the methylation cycle into the sulphation cycle. As a consequence there would be lower production of hydrogen sulfide (see below), iron sulphur proteins (see below), and lower activity of aconitase (see below), all of which are features of AD.
Folate: Folate, or at least 5-methyltetrahydrofolate (5MTHF) is an essential vitamin that works in concert with methionine synthase to regenerate methyl Co(III) B12 from *Co(I) B12, and as such has an essential role in methylation and in the reduction of homocysteine, and production of SAM. Low folate concentrations (below 11.8 nmol/L) have been linked to a 90% greater dementia risk than normal folate concentrations (32,33). Lower folate levels have also been linked to increased accumulation of Tau and increased beta-amyloid levels in the cerebrospinal fluid (CSF) (see below; 34,35).
Vitamin B2: Evidence of reduced activity or dietary lack of vitamin B2 is evident in AD as can be shown by the decreased ratio of reduced:oxidized glutathione (GSH:GSSG) in the brains of AD individuals, due to reduced activity of the FAD-dependent enzyme glutathionine reductase (36). In addition, there are deficiencies in function in the mitochondrial cerebral metabolism with reduced activity seen in the B2 dependent enzymes, pyruvate dehydrogenase (the link between glycolysis and Kreb's cycle), alpha-ketoglutarate dehydrogenase (within Kreb's cycle), and cytochrome C oxidase (the link between Kreb's cycle and the electron transport chain) (37). Altered glucose metabolism with a movement away from glucose as the preferred energy cycle in the brain, has been postulated to result in brain hypometabolism characteristic of AD (37). For some reason, that escapes the group at Preventing Dementia, the role of vitamin B2 in this process has received little attention, despite the obvious implications of a deficiency in vitamin B2 as being a probable cause for deficiency in folate, functional vitamin B12, lower activity of CBS, a deficiency in iron and elevated homocysteine. Further, to date no supplementation studies have been performed with the addition of vitamin B2/B12 and folate for the treatment of dementia. Further, vitamin B2 deficiency is also implicated in obesity and in type II diabetes, two known predisposing risk factors for the development of dementia. Vitamin B2 deficiency is a major contributor to the Autophagic Model of AD
Iron: Whilst there is the potential for iron deficiency to occur due to lack of dietary intake, or because of poor gastro-intestinal uptake this does not explain the presence of iron deposits in the brain of those with AD. If, however, we consider the two findings, lower serum ferritin and higher deposition of iron in the brain, the distinct possibility arises that the brain has been accumulating iron due to a perceived iron lack, but after having imported the iron, the brain cannot use it and so it dumps the iron, which rapidly precipitates due to its low solubility. One potential use for imported iron in the brain is for the assembly of iron-sulphur complexes and for the formation of heme. In order to make iron-sulphur complexes, however, there needs to be a supply of sulphur. Free sulphur for incorporation into Fe-S complexes originates as dietary methionine, and (as mentioned above) the supply of sulphur to the brain in AD will be restricted due to elevated homocysteine. In this regard Zhang and co-workers (38) have shown that levels of the sulphur precursor, cystathionine are very low in the aged brain, as such this would mean that the ability to form iron-sulphur complexes will be limited and so the likelihood is that imported iron cannot be used and so is dumped, thereby leading to the disruption of Iron-sulfur biogenesis and the formation of iron deposits in the brains of persons with AD. (39).Thus, the observed serum ferritin deficiency and local iron precipitation in the brain in AD, could be due to reduced activity of CBS as a result of low iron/B6 and/or vitamin B2. Reduced iron could also explain the reduced activity of cytochrome oxidase seen in the brains of AD patients (40), and the reduced activity of other heme proteins such as glutathione peroxidase and catalase (36),
Aconitase: If we accept that in AD there is a reduced movement of dietary sulphur (from methionine intake) because of a reduced activity of CBS, and we combine that with the iron precipitation (mentioned above), this will logically lead to reduced production of Fe-S complexes with an accompanying drop in aconitase activity (as already shown for AD)(41,42,42). The corollary to this is that there are many other Fe-S proteins in the body, which will also be affected, including succinate dehydrogenase, xanthine oxidase and GABA aminotransferase. Lack of activity of the later enzyme is associated with depression, a common co-morbidity of AD.
Hydrogen sulfide: Accompanying reduced activity of aconitase and the subsequent reduced production of Fe-S complexes, we would also expect to see reduced production of hydrogen sulfide, due to the lower production of cystathionine and cysteine, both of which are features of AD (44,45,46,47,48), and so factors that increase homocysteine levels, reduce aconitase activity and iron-sulphur protein assembly and reduce hydrogen sulfide formation would be expected to be similar.
Acetyl Choline: Several studies have shown evidence of cholinergic degeneration in the cerebral cortex of those with AD (27). Acetylcholine production involves uptake of pre-synthesized choline by neurons and reaction with acetyl CoA to form acetylcholine. Effectively anything that affects production of acetyl-CoA would therefore reduce production of acetyl-CoA. Acetyl-CoA is derived from the break-down of fats, and so a deficiency of vitamin B2 (the active form of which, FAD, is essential for acetyl-CoA dehydrogenase to degrade fatty acids) would reduce levels of fat derived acetyl-CoA. Acetyl-CoA is also derived from the reaction of pyruvate with CoA by pyruvate dehydrogenase (whose activity is altered in AD - see above)(37), so deficiency in vitamin B1, B2 or lipoate will reduce this reaction and lead to the build up of pyruvate, lactate and 2-hydroxybutyrate. This effectively means that in the brain, which normally uses glucose as its energy source, a deficiency of B1 or B2 will lead to lower production of acetyl-CoA, and acetylcholine from glucose, as such the brain will have to resort to energy production from ketones produced by ketogenic amino acids. Such production will be limited in low protein diets. This may explain the association between altered glucose metabolism in type 2 diabetes and the progression of Alzheimer's disease (49) and in contrast explain the beneficial effects of dairy consumption on neurocognitive health during ageing (50).
Beta Amyloid Plaques: These are postulated to be due to improper processing of "amyloid precursor protein to yield beta amyloid". Reduced levels of folate in the brains of AD individuals have been associated with the formation of B-amyloid peptide production, suggesting a role of methylation in reducing B-amyloid formation (34,51,52,53,54)). Further folic acid administration has been shown to inhibit amyloid B-peptide accumulation in mouse models of AD (53).
Neurofibrillary Tangles: A feature of AD is the accumulations of abnormal filaments called neurofibrillary tangles, which are formed by the microtubule-associated protein Tau. One feature of the Tau found in these tangles is that it is hyperphosphorylated, which could explain the alteration in structure leading to tangle formation. In normal brain tissue, Tau is dephosphorylated by an enzyme called phosphoseryl/phosphothreonyl protein phosphatase-2A (PP2A). The activity of this enzyme appears to be controlled by methylation and in conditions of low methylation the enzyme activity drops (55). This would happen in a deficiency of vitamin B12, folate or vitamin B2. In this regard reduction in folate levels with methotrexate has been shown to increase AD pathology and alter Tau phosphorylation (56). Reduced folate and B12 levels in rat brains has been associated with increased Tau accumulation (34). Increased levels of Tau have been found in the CSF of individuals with low folate, elevated Hcy and S-adenosyl-homocysteine, and lower cystathionine (35).
Selenium: There are over 30 selenoproteins in the body, including glutathione peroxidases, phospholipid hydroperoxide, thioredoxin reductase, and iodothyroinine deiodinase. The later protein catalyses the 5,5-mono-deiodination of the prohormone thyroxine (T4) to the active thyroid hormone 3,3'5-triiodothyronine (T3), an essential hormone for the activation of dietary riboflavin (vitamin B2) to the two active forms of the vitamin, FMN and FAD (56). Selenium levels are normally maintained in the brains, despite reduction in serum levels. Studies by Vaz and co-workers (57) found increasing concentrations of iron in the brains of elderly people with Alzheimer disease, which gradually increased as the subjects moved up the Clinical Dementia Rating (CDR) score. In contrast the levels of selenium were found to decrease, with levels in CDR-3 patients being significantly lower than in healthy controls. Lack of local selenium in the brain would reduce the amount of functional vitamin B2 present, which could in turn result in lower levels of active vitamin B12, plus reduced activity of FAD-dependent enzymes in the citric acid cycle, the electron transport chain, and lower activity of pyruvate dehydrogenase, with resultant lowering of production of Acetyl-CoA and acetylcholine.
The potential methods for preventing or even treating dementia/AD will be discussed on the relevant web-page.
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