Original Research

Can Cognitive Deterioration Associated with Down Syndrome be Reduced?

By R. Thiel, Ph.D., Naturopath and S.W. Fowkes, B.A.

Center for Natural Health Research, Down Syndrome-Epilepsy Foundation

1036 W Grand Ave,

Grover Beach, CA 93433


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Thiel R.J., Fowkes S.W. Can cognitive deterioration associated with Down syndrome be reduced? Medical Hypotheses, 2005; 64(3):524-532


Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to slowed and reduced mental development, they are much more likely to have cognitive deterioration and develop dementia at an earlier age than individuals without Down syndrome. Some of the cognitive impairments are likely due to post-natal hydrogen peroxide-mediated oxidative stress caused by overexpression of the superoxide dismutase (SOD-1) gene, which is located on the triplicated 21 st chromosome and known to be 50% overexpressed. However, some of this disability may also be due to early accumulation of advanced protein glycation end-products, which may play an adverse role in prenatal and postnatal brain development. This paper suggests that essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive. Acetyl-L-carnitine, aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have possible safety concerns for this population. This paper hypothesizes that nutritional factors begun prenatally, in early infancy, or later may prevent or delay the onset of dementia in the Down syndrome population. Further examination of this data may provide insights into nutritional, metabolic and pharmacological treatments for dementias of many kinds. As the Down syndrome population may be the largest identifiable group at increased risk for developing dementia, clinical research to verify the possible validity of the prophylactic use of anti-glycation nutrients should be performed. Such research might also help those with glycation complications associated with diabetes or Alzheimer’s.


People with Down syndrome (DS) are much more likely to develop dementia than the general public. While only around 2% of the general public has dementia by age 40 (1), nearly all of those with DS show signs of an Alzheimer’s-like dementia prior to age 40 (2).

In DS (also known as trisomy 21), there is an extra copy of the 21st chromosome. Many enzymes that are encoded on the extra 21st chromosome are known to be actively transcribed, which results in overexpression of these enzymes. Genetic overexpression of enzymes leads to overconsumption of their enzymatic substrates and overproduction of their metabolic end-products. One of the best documented examples of this phenomenon in Down syndrome is the SOD-1 gene, which is approximately 50% overexpressed (3,4). Elevated levels of cytosolic superoxide dismutase decrease the levels of superoxide (the enzyme's substrate) and increase the levels of hydrogen peroxide (the enzyme’s metabolite, end-product or output). These primary consequences of genetic overexpression may then produce secondary metabolic adaptations as homeostatic systems attempt to compensate. As an example, increased levels of hydrogen peroxide might induce the production of glutathione peroxidase, a selenium-dependent enzyme, and thereby increase selenium requirements (5). Such genetically driven, enzymatic and metabolic disturbances may help explain why individuals with DS are more likely than those without it to develop various forms of dementia (2).

Glycation as a Possible Cause

Glycoxidation damage appears to begin in those before birth who have DS, but not for those that do not (6). A trial involving human fetuses of between 18-20 weeks of gestation found increased levels of oxidation markers pyrraline and pentosidine, both of which are well known end-products of nonenzymatic glycation that tend to accumulate in aging tissues; amyloid beta (Abeta) peptides were also found (6). “In persons with Down syndrome, soluble Abeta peptides, which result from the processing of the amyloid precursor protein, appear in the brain decades before the extracellular deposition of neuritic plaques. These soluble amyloidogenic peptides accumulate intraneuronally and can be secreted extracellularly. Their appearance has been reported in the brains of fetuses with Down syndrome, but not non-DS fetuses. The extra gene dosage effect associated with trisomy 21 results in abnormalities of the processing of amyloid precursor protein in persons with Down syndrome” (7). It is possible that this may account for some (or even much) of the characteristically slowed mental development for this population. There are multiple causal relationships to consider. The increased magnitude of amyloid induction may be a direct manifestation of a genetic overexpression. It is also possible, or even maybe likely, that the effect of the gene overdose on amyloid metabolism is indirect and a consequence of mechanisms of prolonged oxidative stress or chronic inflammation.

For example, it has been reported that both bradykinin B2 receptor modification and bradykinin mediated tau Ser phosphorylation can be detected in the fibroblasts of people with DS two decades before the characteristic onset of Alzheimer’s dementia (8). Increased Ser phosphorylation of tau microtubule-associated protein in the brain is an early feature of Alzheimer’s that tends to precede neuronal disruption (8). It appears that nitrative (nitrate-mediated) injury is directly linked to the formation of filamentous tau inclusions and the subsequent neurodegeneration of those with DS and those with Alzheimer’s (9). People with DS over 40 years of age, prematurely and consistently develop neurofibrillary tangles, intracytoplasmic inclusions of highly insoluble straight or paired helical 12-16 nm filaments, and senile plaques composed of abnormal neurites surrounding a core of beta amyloid. These two lesions occur in distributions similar to those seen in Alzheimer disease (2).

Deutsch et al reported, “Abeta peptides, especially Abeta1-42, have been shown to form tight complexes with the alpha7 nicotinic acetylcholine receptor, interfering with transduction of the acetylcholine signal by this nicotinic receptor subtype. Furthermore, the selective binding of Abeta peptides by this nicotinic acetylcholine receptor subtype is associated with cytotoxicity. The alpha7 nicotinic acetylcholine receptor has unique electrophysiologic properties and plays a prominent role in normal psychophysiologic processes (eg, sensory inhibition) and cognition. In persons with Down syndrome there is a decrease in the ability to perform instrumental activities of daily living that worsen with aging (7).” While Russo et al reported that “N-terminally truncated amyloid-beta (Abeta) peptides are present in early and diffuse plaques of individuals with Alzheimer's disease (AD), are overproduced in early onset familial AD and their amount seems to be directly correlated to the severity and the progression of the disease in AD and Down's syndrome (DS)” (10), then in another paper concluded “The carboxy-terminal fragments (CTFs) of the amyloid precursor protein…constitute in human brain a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.” (11) Thus, it seems reasonable that Abeta could be a contributor to what we see in Down syndrome. It may be of interest to note that diabetics also have problems with protein glycation and related end-products (12).

Nutrition as an Intervention Strategy

Glycoxidation is “a process that occurs with elevated blood glucose levels. Another pathway that results in the modification of LDL proteins involves the formation of Amadori products. An adequate amount of antioxidants from the diet or supplements may help prevent or delay the occurrence of diabetic late syndrome” (13). Or as Price et al have worded it, “The Maillard or browning reaction between sugars and proteins leads to the formation of chemical modifications and cross-links in proteins, known as advanced glycation end-products (AGEs). These products contribute to the age-dependent chemical modification of long-lived proteins, and accelerated formation of AGEs during hyperglycemia is implicated in the development of diabetic complications” (14).

Various sugars react with amino groups in proteins and nucleic acids to produce advanced glycation end products (15). As glycation end-products tend to accumulate as the result of disorders of sugar metabolism such as diabetes, it is possible that a diet low in refined carbohydrates may be a logical choice for those with DS (diets naturally high in vitamin C have been shown to result in reduced protein glycation (16)). Although this would not stop all glycation end-products from forming and accumulating, it may significantly reduce their formation and possibly delay the onset of discernable dementia symptoms in the DS population.

Since glycation of long-half-life proteins, involving carbohydrates, leads to the formation of intra and intermolecular cross-links and the production of free radicals (17), it is likely that antioxidants would have potential therapeutic value.


Folate Children with DS often have below-normal levels of folate (18-20). Erythrocyte macrocytotis is more common in children and adults with DS and may be due to an alteration of the folate remethylation pathway (16)—whether this is due to trisomy or to maternal genetic MTHFR (methyltetrahydrofolate reductase) status in utero is unclear. As those with DS age, further declines in folate levels seem to occur (21). An animal study found that restricting folate, vitamin B6, and vitamin B12 resulted in an increased formation of methionine related advanced glycation end-products (22). Methionine is particularly sensitive to oxidation from hydroxyl radicals (23).

The dietary source and chemical form of folate may also play a role. Naturally occurring folate, as found in vegetable foods, has been reported to have less affinity for serum folate-binding proteins than does purified folate supplied in nutritional supplements (24). However, it is also true that the most common kind of folate in dietary supplements is folic acid, and only about 266mcg to 400 mcg of folic acid can be converted into methylfolate per day (24,25). It is possible that accumulation of unconverted folic acid may have potentially adverse affects on folate metabolism (24,25). However, folate “trapping,” caused by impaired interconversion between the seven biologically active forms of folate, does causes accumulation of some form(s) of folate and simultaneous depletion of other form(s), which does adversely affect folate-dependent metabolic pathways (26,27,28). So there may be unappreciated advantages to either food-based folate or folate supplements containing other biologically active folate compounds.

Vitamin B6 A three-year double-blind placebo-controlled longitudinal DS study found that vitamin B6 supplementation helped normalize brain function by reducing elevated cortical auditory evoked potentials to a more normal level (29). Vitamin B6 deficiency has been associated with impairments in gluconeogenesis and abnormal glucose intolerance. It has been recommended to help deal with glycation (23,29). Furthermore, it or its derivatives have been shown to have anti-glycation effects (14,15). A compound containing it and aminoguanidine has been shown to be more effective in reducing glycation than aminoguanidine alone (30), but the safety of such non-food compounds needs extensive research. The safety of foods containing vitamin B6 and supplements containing anti-metabolite-free B6 has been well established. However, ordinary B6 supplements containing food-grade and pharmaceutical-grade B6 have been historically associated with scattered clinical reports of peripheral neuropathy and may have contained sufficient levels of B6 antimetabolites to pose a neurological hazard at doses of B6 exceeding 50-500 mg/day. Other clinical reports have noted that extended use if 2000-6000 mg/day doses of high-purity B6 do not cause peripheral neuropathy.

Vitamin C One study found that many children with DS had a deficiency of vitamin C according to serum tests (31). A case report found the same result (32), yet a small study found that institutionalized children with DS tended to consume more vitamin C than the recommended daily allowance (33), thus suggesting that perhaps more is needed in the DS population. Vitamin C appears to be an antiglycation agent (13,34-36).

The type and/or source of vitamin C (or at least associated food factors) may make a difference. A human study found that a citrus food complex containing 500mg of vitamin C was 216% more effective in reducing sorbitol in diabetics, 42% more effective in reducing protein glycation, and 41% more effective in decreasing galactiol when cataracts are present than isolated USP ascorbic acid (34). One study by Vinson and Howard showed an average decrease of 46.8% in protein glycation after four weeks using 1000mg per day of vitamin C complexed in citrus food (35), while a study by Davie, Gould, and Yudkin only had a 33% reduction in three months using 1000mg of isolated ascorbic acid per day (36). Foods contain both ascorbate and dehydroascorbate forms of vitamin C, and dehydroascorbate has been found to be a potent antiglycation agent (37). Furthermore, an in vitro study found that citrus containing vitamin C has negative ORP (oxidation-reduction potential) while isolated ascorbic acid has positive ORP (38) (negative ORPs indicate active reducing power, which is immediately capable of antioxidant activity, whereas items with positive ORPs are not). The Merck Index also states that isolated ascorbic acid has positive redox potential (1). However, since ORP is significantly pH dependent and none of these ORP readings controlled for pH differences, more research in this area is needed.

Vitamin E One study found that children with Down syndrome have significantly less vitamin E levels than those without it (39). Down syndrome patients with dementia have lower plasma levels of vitamin E than those that do not (40). It is reported that vitamin E appears to be an anti-glycation agent (13,41).

Chemical form and source may play a role as “chemically synthesized alpha-tocopherol is not identical to the naturally occurring form” (42). By weight, vitamin E as natural RRR-alpha-tocopherol has 1.7 - 4.0 times the peroxyl-radical-scavenging-activity of the other tocopherols, RRR-alpha tocopherol has 3 times the biological activity of the alpha-tocotrienol form, and vitamin E acetate (a synthetic form) simply does not have the same biologic activity of natural vitamin E (some synthetic forms have only 2% of the biological activity of RRR-alpha-tocopherol) (42). It should be pointed out, however, that mixtures of different forms of vitamin E have a broader range of free-radical-scavenging abilities than any purified or single form of vitamin E. Vitamin E in food seems to be retained 7.02 times better than isolated alpha-tocopherol acetates (43), thus it may be the preferred way to help prevent glycation. High-vitamin-E food has also been shown to prevent glycation (44).

Selenium DS patients may have below-normal plasma levels of selenium (45,46). This may be a direct consequence of increased incorporation of selenium into glutathione peroxidase, which is induced to higher-than-normal levels by excessive SOD-mediated hydrogen peroxide production. Selenium may be beneficial in DS by protecting the biosynthesis of thyroxine from free radical attack (47). Selenoenzymes also catalyze the iodination of tyrosine residues in the manufacture of T4 and T3, and regulate the tissue conversion of T4 into T3.

Selenium has not generally been considered much of an anti-glycation agent, but this may be because most common selenium forms in supplements are not in the biologically active form (i.e., “Factor 3,” as naturally occurs in liver) and have little proven anti-glycation effects. However, yeast grown in high-selenium media has been found to produce significant anti-glycation effects as a dietary supplement. One study found that high-selenium yeast was 123 times more effective than selenomethionine in preventing nonenzymatic glycation in diabetics (44). This same study found that high-selenium yeast was more effective in glycation prevention than ascorbic acid, niacinamide, carnosine, tocopherol, and pyridoxal (44).

Another study using 247 mcg/day of high-selenium yeast found that plasma selenium levels were 2-fold higher than baseline values after 3 and 9 months and returned to 136% of baseline after 12 months, whereas there was a 32% increase in blood glutathione levels also seen after 9 months. This change coincided with a 26% decrease in protein-bound glutathione and a 44% decrease in the ratio of protein-bound glutathione to blood glutathione. The changes in glutathione and protein-bound glutathione were highly correlated with changes in plasma selenium levels and were believed to reflect a reduction in oxidative stress (48). However, cellular selenium levels were not determined, nor were any seleno-enzyme activities measured. So further research is needed to clarify the advantages of high-selenium yeast.

Zinc Reports suggest that DS patients have below-normal plasma levels of zinc (49,50). While diabetics often also have zinc deficiency, this deficiency may be refractory to mineral salt zinc supplements (12). Even though high-zinc yeast has been shown to be 6.46 times more absorbed into the blood than zinc gluconate (51), zinc helps with diabetic complications (52), and zinc is highly recommended to assist with oxidative stress (53). It is not clear that zinc has any significant effect on preventing accumulation of advanced protein glycation end-products. However, since zinc can reduce copper in some tissues (54), individuals with DS have frequently been found to be high in copper in various measurements (40), and zinc and copper compete with each other for enzyme binding, zinc should not be overlooked in DS. Future research into copper-zinc dynamics is warranted.

Other Substances

Acetyl-L-carnitine At least in eyes, it appears that acetyl-L-carnitine may have antiglycation abilities (55). Hendlor and Rorvik report, “”Acetyl-L-carnitine has recently demonstrated some efficacy as a possible neuroprotective agent for strokes, Alzheimer’s disease, Down’s syndrome and for the management of various neuropathies…recent studies show beneficial effects in Alzheimer’s disease. Younger patients seem to benefit most” (55). However, some few with seizure disorders have reported increases in seizure frequency or severity on acetyl-L-carnitine (54). As the DS population is much more inclined towards seizure disorders than the general public (56), caution would seem to be advisable regarding using acetyl-L-carnitine to attempt to prevent glycation.

Alpha-Lipoic Acid Alpha-lipoic acid, also known as thioctic acid, appears to have anti-glycation abilities (57,58). Alpha-lipoic acid may act to limiting cofactors in the product of advanced protein glycation end products (58). Animal research suggests that it may have anti-aging effects (53).

Aminoguanidine Aminoguanidine may be one of the most powerful substances with anti-glycation abilities (14,30). However, since it has the effect of greatly reducing the vitamin B6 from the body, it may not be safe enough for use in the DS population—which tends to be deficient in vitamin B6 (56). A pyridoxal-containing form is being tested (30).

Carnosine Serum carnosine deficiency is a rare condition, which is not often clinically assessed. Symptoms of serum carnosine deficiency are similar to some often associated with DS such as mental retardation, absence seizures, and childhood dementia (59). Carnosine and related compounds (such as homocarnosine) have been found to have protective effects against hydrogen peroxide-mediated Cu,Zn-superoxide dismutase fragmentation (60) and SOD-1mutants (61) which may cause problems for those with DS. Carnosine is also an antiglycation agent that may prevent or at least reduce this brain damage (62). A recent study concluded “that carnosine and such related compounds as Gly-His and Ala-His are effective anti-glycating agents for human Cu,Zn-SOD and that the effectiveness is based not only on high reactivity with carbonyl compounds but also on hydroxyl radical-scavenging activity” (63). Furthermore involving heat, carnosinylation tags glycated proteins for cell removal (64); it also appears to have anti-inflammatory properties, which may be due to its anti-glycation abilities (65). Carnosine has even been proposed as a possible “anti-dementia drug” (66).

Cysteine People with DS have been found to have abnormally high levels of cysteine (67). This is likely due to the overexpression of cystathionine-beta-synthase, which diverts homocysteine into cysteine, thus preventing it from being recycled (remethylated) into methionine within the S-adenosylmethionine (SAM) cycle. This may be why abnormally high levels of cathepsin S (a lysosomal cysteine protease) have been found, postmortem, in those with DS and Alzheimer’s (68). Despite this, a study of mice with trisomy 16 (a mouse model for human Down syndrome) found that N-acetyl-cysteine reduced toxicity believed similar to that caused by the oxidative stress of triplication of superoxide dismutase (69). Since N-acetyl-cysteine is an anti-glycation agent (70), it may be of interest for use in the DS population. However, since L-cysteine can induce seizures (71,72), and there is also a case report of status epilepticus being induced by the injection of N-acetylcysteine (73) , it may have only limited possible use.


It is speculated that the presence of advanced glycation end-products in the fetal brain are not significant enough to stop, but may slow down, brain differentiation and development. It is logical to conclude that increases in brain size during growth may partially explain why those with DS do tend to make developmental progress, though at a much slower pace than the non-trisomy population. Although glycation accumulation in DS appears be markedly slower than that which occurs with Alzheimer’s disease, the accumulation appears to begin at the earliest stages of life, which is in distinct contrast to the accumulation seen in Alzheimer’s disease. The early accumulation of advanced glycation end-products appears to finally result in dementia in much of the DS population.

Similarly, Deutsch et al observed, “The progressive worsening of adaptive functions and cognition in persons with Down syndrome may be, at least in part, mediated by interference with [the alpha7 nicotinic acetylcholine] receptor by soluble Abeta peptides...Ideally, selective cholinergic interventions would slow the progression of the worsening of adaptive function and emergence of dementia in persons with Down syndrome” (7). Anti-glycation agents may be a way to accomplish that.

Stadtman and Levine noted that, “the accumulation of oxidized protein is a complex function of the rates of ROS [reactive oxygen species] formation, antioxidant levels, and the ability to proteolytically eliminate oxidized forms of proteins. Thus, the accumulation of oxidized proteins is also dependent upon genetic factors and individual life styles” (23). Although it is unclear how anti-glycation agents precisely work, heat (65) and antioxidant properties (17,23), anti-inflammatory properties (66) and other pathways have been proposed. Price et al “conclude that both carbonyl trapping and chelation activity of AGE inhibitors and AGE-breakers may be involved in their therapeutic mechanism of action (14). Price et al also concluded “All AGE inhibitors studied were chelators of copper…AGE inhibitors have significant copper chelating activity” (14). As those with DS have often been found to have excesses of copper in certain metabolic compartments (40,45,48), it appears quite plausible that anti-glycation agents could be either reducing copper toxicity or counteracting copper sequestration mechanisms as a mechanism of action. Either way, anti-AGE therapies could prove to be a legitimate treatment for those with DS.

The efficacy of multi-nutrients in DS alone, though advocated by some (i.e. 74-76), has been discounted by others (i.e.77-79)—but none have looked into anti-glycation therapies, nor into the use of high-nutrient foods for enhancing nutritional status. High-nutrient foods may have significantly higher antioxidant properties in vivo compared with isolated or synthetic anti-oxidant nutrients (35,38), which may be, in key instances, not even in the same biochemical form as those found in food (80).

Irrespective of these controversies, a review of the nutrients and metabolic end-products shown above suggests that it is logical that certain nutrients may be preventive for key pathological processes involved in dementias, such as DS and Alzheimer’s. Furthermore, considering the relative safety and theoretical benefits of the above-mentioned nutrients, as well as the inevitability of accumulations of advanced protein glycation end-products in the untreated DS population, it seems wise to seriously consider such supplementation. It seems equally wise to undertake additional research to verify the safety and efficacy of such substances as acetyl-L-carnitine, aminoguanidine, cysteine, and N-acetylcysteine in the DS population. Other substances mentioned and not mentioned in this paper may also be of value.

Glycation end-products also tend to accumulate in the brains of those who develop Alzheimer’s or similar forms of dementia (81). It is possible that these accumulations play only a small role in cognitive decline, but it appears reasonable to conclude that any “sticky plaque on the brain” is not mentally helpful (especially as this does not tend to occur in the non-DS, non-Alzheimer’s populations).

The predictable and consistent appearance of the Alzheimer’s-like neuropathologic changes in DS provides an unusual opportunity to examine the sequential development of advanced protein glycation end-products and their consequences (1). As the DS population is probably the largest identifiable group for developing dementia, clinical research to verify the possible validity of the prophylactic food-born nutrients, use of anti-glycation agents for this population should be performed--specifically including food-bound nutrients, folate, vitamin B6, vitamin C, vitamin E, selenium and zinc, along with alpha-lipoic acid and carnosine. Such research may not only benefit those with DS, but would also be expected to have benefit for others at risk for Alzheimer’s and other forms of dementia (63,81). It may also be of benefit to those with certain complications associated with diabetes.


  1. Beers MK, Berkow R, editors. The Merck Manual, 17th ed. Whitehouse Station (NJ): Merck Research Laboratories, 1999
  2. Cork LC. Neuropathology of Down syndrome and Alzheimer disease. Am J Med Genet Suppl. 1990;7: 282-286
  3. Sinet PM. Metabolism of oxygen derivatives in Down’s syndrome. Ann NY Acad Sci. 1982;185:83-94
  4. Anneren G, Edman B. Down syndrome-a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of the effects from the superoxide type-1 (SOD-1) gene. AMPIS Suppl. 1993;40: 71-79
  5. Antila E, Norberg U-R, Syvaoja E-L, Wetermarck T. Selenium therapy in Down syndrome: a theory and clinical trial. In Antioxidants in Therapy and Preventative Medicine. New York: Plenum Press, pp. 183-186, 1990
  6. Odetti P, Angelini G, Dapino D, Zaccheo D, Garibaldi S, Dagna-Bricarelli F, Piombo G, Perry G, Smith M, Traverso N, Tabaton M. Early glycoxidation damage in brains from Down's syndrome.Biochem Biophys Res Commun. 1998;243(3):849-851
  7. Deutsch SI, Rosse RB, Mastropaolo J, Chilton M. Progressive worsening of adaptive functions in Down syndrome may be mediated by the complexing of soluble Abeta peptides with the alpha7 nicotinic acetylcholine receptor: therapeutic implications. Clin Neuropharmacol. 2003;26(5):277-283
  8. Jong YJ, Ford SR, Seehra K, Malave VB, Baenziger NL. Alzheimer’s disease skin fibroblasts selectively express a bradykinin signalling pathway mediating tau protein Ser phosphorylation. FASEB J. 2003;17(15): 2319-2321
  9. Horiguchi T, Uryu K, Giasson BI, Ischiropoulos H, LightFoot R, Bellmann C, Richter-Landsberg C, Lee VM, Trojanowski JQ. Nitration of tau protein is linked to neurodegeneration in tauopathies.Am J Pathol. 2003;163(3):1021-1031
  10. Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, Benatti U, D'Arrigo C, Patrone E, Carlo P, Schettini G. Pyroglutamate-modified amyloid beta-peptides--AbetaN3(pE)--strongly affect cultured neuron and astrocyte survival. J Neurochem. 2002;82(6):1480-1489
  11. Russo C, Salis S, Dolcini V, Venezia V, Song XH, Teller JK, Schettini G. Amino-terminal modification and tyrosine phosphorylation of [corrected] carboxy-terminal fragments of the amyloid precursor protein in Alzheimer's disease and Down's syndrome brain. Neurobiol Dis. 2001;8(1):173-180
  12. Cunningham JJ. Micronutrients as nutriceutical interventions in diabetes mellitus. J Am Coll Nutr. 1998;17(1):7-10
  13. Meli M, Frey J, Perier C. Native protein glycoxidation and aging. J Nutr Health Aging. 2003;7(4):263-266
  14. Price DL, Rhett PM, Thorpe SR, Baynes JW. Chelating activity of advanced glycation end-product inhibitors. J Biol Chem. 2001;276(52):48967-48972
  15. Stahl W, Sies H, Antioxidant Defense: Vitamins E and C and Carotenoids. Diabetes. 1997;46(Suppl.2):S14-S18
  16. Boeing H, Weisgerber UM, Jeckel A, Rose HJ, Kroke A. Association between glycated hemoglobin and diet and other lifestyle factors in a nondiabetic population: cross-sectional evaluation of data from the Potsdam cohort of the European Prospective Investigation into Cancer and Nutrition Study. Am J Clin Nutr. 200071(5):1115-1122
  17. Leslie RD , Beyan H, Sawtell P, Boehm BO, Spector TD, Snieder H. Level of an advanced glycated end product is genetically determined: a study of normal twins. Diabetes. 2003;52(9):2441-2444
  18. David O, Fiorucci GC, Tosi MT, Altare F, Valori A, Saracco P, Asinardi P, Ramenghi U, Gabutti V. Hematological studies in children with Down syndrome. Pediatr Hematol Oncol. 1996:271-275
  19. Ibarra B, Rivas F, Medina C, Franco ME, Romero-Garcia F, Enrique C, Galarza M, Hernandez-Cordova A, Hernandez T. Hematological and biochemical studies in children with Down syndrome. Ann Genet. 1990;33(2):84-87
  20. Wachtel TJ, Pueschel SM. Macrocytosis in Down syndrome. Am J Ment Retard. 1991;95(4):417-420
  21. Gericke GS, Hesseling PB, Birnk S, Tiedt FC. Leukocyte ultrastructure and folate metabolism in Down’s syndrome. S Afr Med J. 1977;51(12):369-374
  22. Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107(6): 675-683
  23. Stadtman ER, Levine RL. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids. 2003;25(3-4):207-218
  24. Herbert V. Folic Acid. In Modern Nutrition in Health and Disease, 9th ed. Williams & Wilkins, Balt.,1999:433-446
  25. Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ, 2004;328:211-214
  26. Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ. Homocysteine metabolism in children with Down syndrome: in vitro modulation. Am J Hum Genet. 2001; 69(1): 88-95
  27. James SJ, Pogribna M, Pogribny IP, Melnyk S, Jine RJ, Gibson JB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr. 1999; 70(4): 495-501
  28. Hobbs CA, Cleves MA, Lauer RM, Burns TL, James SJ. Preferential transmissionm of the MTHFR 677 T allele to infants wityh Down syndrome: implications for a survival advantage. Am J Med Genet. 2002 Nov 15; 113(1): 9-14.
  29. Frager J, Barnet A, Weiss I, Coleman M. A double blind study of vitamin B6 in Down’s syndrome infants. J Ment Def Res. 1985;29(Pt3):241-246
  30. Miyoshi H, Taguchi T, Sugiura M, Takeuchi M, Yanagisawa K, Watanabe Y, Miwa I, Makita Z, Koike T. Aminoguanidine pyridoxal adduct is superior to aminoguanidine for preventing diabetic nephropathy in mice. Horm Metab Res. 2002;34(7):371-377
  31. Colombo ML, Girardo E, Incarbone E, Conti R, Ricci BM, Maina D. Vitamin C in children with trisomy 21. Minerva Pediatr. 1989;41(4):189-192
  32. Hilty N, Sepp N, Rammal E, Pechlaner C, Hintner H, Fritsch P. Scurvy in trisomy 21. Hautarzt. 1991;42(7):464-466
  33. Chad K, Jobling A, Frail H. Metabolic rate: a factor of developing obesity in children with Down syndrome? Am J Ment Retard. 1990;95(2):228-235
  34. Vinson JA, et al. In vitro and in vivo reduction of erythrocyte sorbitol by ascorbic acid. Diabetes. 1989;38:1036-1041
  35. Vinson JA, Howard TB. Inhibition of protein glycation and advanced glycation end products by ascorbic acid and other vitamins and nutrients. Nutr Bioch. 1996;7:659-663
  36. Davie SJ, Gould BJ, Yudkin JS. Effect of vitamin C on glycation of proteins. Diabetes. 1992;41:161-173
  37. Argirov OK, Lin B, Olesen P, Ortwerth BJ. Isolation and characterization of a new advanced glycation endproduct of dehydroascorbic acid and lysine.Biochim Biophys Acta. 2003;1620(1-3):235-44
  38. Thiel R. The truth about vitamins in supplements. ANMA Monit. 2003;6(2):6-14
  39. Cengiz M, Seven M. Vitamin and mineral status in Down syndrome. Trace Elem Elec. 2000;17(3):156-160
  40. Werbach M. Down syndrome. In Textbook of Nutritional Medicine. Tarzana (CA): Third Line Press, pp. 340-348, 1999
  41. Ceriello A, Giugliano D, Quatraro A, Dello Russo P, Torella R. A preliminary note on inhibiting effect of alpha-tocopherol (vit. E) on protein glycation. Diabete Metab. 1988;14(1):40-42
  42. Traber MG. Vitamin E. In Modern Nutrition in Health and Disease, 9th ed. Williams & Wilkins, Balt.,1999:347-362
  43. Thiel R. Food vitamin E is superior. ANMA Monit. 2001;5(3):6-9
  44. Vinson JA, Howard TB. Inhibition of protein glycation and advanced glycation end products by ascorbic acid and other vitamins and nutrients. Nutr Biochem. 1996;7:659-663
  45. Kadrobova J, Madaric A, Sustrova M, Ginter E. Changed serum element profile in Down’s syndrome. Biol Trace Elem Res. 1996;54(3):201-206
  46. Monteiro CP, Varela A, Pinto M, Neves J, Felisberto GM, Vaz C, Bicho MP, Laires MJ. Effects of an aerobic training program on magnesium, trace elements and antioxidant systems in Down syndrome population. Magnes Res. 1997;10(1):65-71
  47. Kanavin OJ, Aaseth J, Birketvedt GS. Thyroid hypofunction in Down's syndrome. Is it related to oxidative stress? Biol Trace Elem Res. 2000;78:35-42.
  48. El-Bayoumy K, Richie JP Jr, Boyiri T, Komninou D, Prokopczyk B, Trushin N, Kleinman W, Cox J, Pittman B, Colosimo S. Influence of Selenium-Enriched Yeast Supplementation on Biomarkers of Oxidative Damage and Hormone Status in Healthy Adult Males: A Clinical Pilot Study. Cancer Epidemiol Biomarkers Prev. 2002;11:1459-1465
  49. Purice M, Maximillan C, Dumitru I, Ioan D. Zinc and copper in plasma and erythrocytes of Down’s syndrome children. Endocrinologie. 1988;26(2):113-117
  50. Sherman AR. Zinc, copper and iron nurtiture and immunity. J Nutr. 1992;122:604-609
  51. Vincent J, Bose P, Lemoine L, Hsaio K. Bioavailability studies. In Nutrient Availability: Chemical and Biological Aspects. Royal Society of Chemistry, Cambridge ( UK), 1989:125-127
  52. Faure P. Protective effects of antioxidant micronutrients (vitamin E, zinc and selenium) in type 2 diabetes mellitus. Clin Chem Lab Med. 2003;41(8):995-998
  53. Stehbens WE. Oxidative stress, toxic hepatitis, and antioxidants with particular emphasis on zinc. Exp Mol Pathol. 2003;75(3):265-276
  54. Hendlor SS, Rorvik D, eds. PDR for Nutritional Supplements. Medical Economics. Montvale (NJ) 2001
  55. Swamy-Mruthinti S, Carter AL. Acetyl- L -carnitine decreases glycation of lens proteins: in vitro studies. Exp Eye Res. 1999;69(1):109-115
  56. Thiel R, Fowkes SW. Down syndrome and epilepsy: A nutritional connection? Med Hypo. 2004; 62(1):35-44
  57. Deuther-Conrad W, Loske C, Schinzel R, Dringen R, Riederer P, Munch G. Advanced glycation endproducts change glutathione redox status in SH-SY5Y human neuroblastoma cells by a hydrogen peroxide dependent mechanism. Neurosci Lett. 2001;312(1):29-32
  58. Munch G, Kuhla B, Luth HJ, Arendt T, Robinson SR. Anti-AGEing defences against Alzheimer's disease. Biochem Soc Trans. 2003;31(Pt 6):1397-1399
  59. Cohen M, Hartlage PL, Krawiecki N, Roesel RA, Carter AL, Hommes FA. Serum carnosinase deficiency: a non-disabling phenotype? J Ment Defic Res. 1985;29( Pt 4):383-389
  60. Choi SY, Kwon HY, Kwon OB, Kang JH. Hydrogen peroxide-mediated Cu,ZN-superoxide dismutase fragmentation: protection by carnosine, homocarnosine and anserine. Biochim Biophys Acta. 1999;1472(3):651-657
  61. Kang JH, Eum WS. Enhanced oxidative damage by the familial amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutants. Biochim Biophys Acta. 2000;1524(2-3):162-170
  62. Brownson C, Hipkiss AR. Carnosine reacts with a glycated protein. Free Radic Biol Med. 2000;28(10):1564-1570
  63. Ukeda H, Hasegawa Y, Harada Y, Sawamura M. Effect of carnosine and related compounds on the inactivation of human Cu,Zn-superoxide dismutase by modification of fructose and glycolaldehyde. Biosci Biotechnol Biochem. 2002;66(1): 36-43
  64. Yeargans GS, Seidler NW. Carnosine promotes the heat denaturation of glycated protein. Biochem Biophys Res Commun. 2003;300(1):75-80
  65. Seidler NW, Yeargans GS. Effects of thermal denaturation on protein glycation. Life Sci. 2002 Mar 1;70(15):1789-1799
  66. Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G. AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology. 2001;2(1):19-34.
  67. Lejeune J, Rethore MO, de Blois MC, Peeters M, Naffah J, Megarbane A, Cattaneo F, Mircher O, Rabier D, Parvey P, et al. Amino acids and trisomy 21. Ann Genet. 1992;35(1):8-13
  68. Lemere CA , Munger JS, Shi GP, Natkin L, Haass C, Chapman HA, Se DJ. The lymsomal cysteine protease, cathespin S, is increased in Alzheimer’s and Down syndrome brain. Am J Pathology. 1995;146(4):848-860
  69. Behar TN , Colton CA. Redox regulation of neuronal migration in a Down Syndrome model. Free Radic Biol Med. 2003;35(6): 566-575
  70. Gasic-Milenkovic J, Loske C, Munch G. Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimers Dis. 2003;5(1):25-30
  71. Yamamoto H. Preventive effect of N(G)-nitro-L-arginine against L-cysteine-induced seizures in mice. Toxicol Lett. 1996;84(1):1-5
  72. Yamamoto H, Tang H. Melatonin attenuates L-cysteine-induced seizures and lipid peroxidation in the brain of mice. J Pineal Res. 1996;21(2):108-113
  73. Hershkovitz E, Shorer Z, Levitas A, Tal A. Status epilepticus following intravenous N-acetylcysteine therapy. Isr J Med Sci. 1996;32(11):1102-1104
  74. Turkel H, Nusbaum I. Medical Treatment of Down Syndrome and Genetic Diseases, 4th ed. Southfield (MI): Ubiotica, 1985
  75. Rimland B. Vitamin/mineral supplementation for Down syndrome. Lancet. 1983;2:1255
  76. Thiel R. Growth effects of the Warner protocol for children with Down syndrome. J Orthomolec Med. 2002;17(1):42-49
  77. Bumbalo TS, Morelewicz HV, Berens DL. Treatment of Down’s syndrome with the “U” series of drugs. JAMA. 1964;187:361
  78. Harrell RF, Capp RH, Davis DR, Peerless, Ravitz LR. Can nutritional supplements help mentally retarded children? Proc Natl Acad Scie. 1981;78:574-578
  79. Pruess JB, Fewell RR, Bennett FC. Vitamin therapy and children with Down syndrome: a review of the research. Except Child. 1989;55:336-341
  80. Thiel R. Natural vitamins may be superior to synthetic vitamins. Med Hypo. 2000;55(6):461-469
  81. Rottkamp CA, Nunomura A, Raina AK, Perry G, Smith MA. Oxidative stress, antioxidants, and Alzheimer’s Disease. Alzheimer Dis Assoc Disord. 2000;14(S1):S62-S66