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December 2003

Elevated Homocysteine Raises Risk of Stroke, Dementia
Protecting Your Brain and Heart Through Folic Acid and B Vitamin Supplementation
By Carmia Borek, Ph. D.

Physical changes in the brain. Elevated homocysteine in Alz-heimer’s disease is associated with atrophy of the temporal medial lobe of the brain, the site of the hippocampus. Other studies show a relation between increased plasma homocysteine and a significant decrease in the width of the cerebral cortex and the width and volume of the hippocampus.4

Folate, B Vitamins Key to Prevention
A basic regimen of folate and B- vitamin supplementation has been shown effective in preventing hyperhomocysteinemia.

Folate and folic acid. Folate is found in foods such as green leafy vegetables, legumes, citrus fruits, grain, berries, and liver; folic acid is the form in which folate appears in supplements and fortified foods. Dietary folate from a mixed diet, however, has a 50% lower bioavailability than synthetic folic acid.12

Vitamin B6. Requirements for vitamin B6 rise with increased intake of protein. The richest dietary sources of vitamin B6 include chicken, fish, liver, and eggs; other sources are soybean, oats, whole wheat products, peanuts, and walnuts. Dairy products and red meat are relatively poor sources of vitamin B6.12

Vitamin B12. Vitamin B12 or cobalamin, a cofactor with folate in the recycling of homocysteine to methionine, is essential in many aspects of human metabolism. Bacteria, fungi, and algae synthesize vitamin B12 but yeasts, higher plant forms, and animals cannot. Animal products are the source of vitamin B12 in the human diet.12

The therapeutic effects of folic acid and B-vitamin supplementation were reported in a recent Austrian study, in which 9 of 31 patients with dementia and hyperhomocysteinemia were treated with 50 mg of vitamin B1, 50 mg of vitamin B6, 5000 mcg of folic acid, and 5 mcg of vitamin B12. After four weeks of treatment, serum homocysteine concentrations returned to normal in all nine patients, dropping from 17.3 to 10.7 micromoles/liter.13

Vegetarians, especially vegans, are at a high risk for vitamin B12 deficiency, which can lead to anemia, elevated homocysteine levels, and irreversible neurological damage. A one-year study of healthy vegetarians found that while all subjects exhibited low levels of vitamin B12, these levels were inversely related to the amount of animal (e.g., dairy) products they consumed. While vegans had the lowest vitamin B12 levels and the highest concentrations of plasma homocysteine, those who took vitamin supplements had plasma vitamin B12 concentrations similar to those of non-vegetarians. The study also found that vitamin B12 levels declined and homocysteine levels increased with advancing age.14

Antioxidants Counter Risk of Dementia
Oxidative stress and neuronal apoptosis are pathological features in dementia; the presence of amyloid beta peptide, a feature of Alzheimer’s dementia, increases neurotoxicity. Antioxidants thus have an important role in blocking these oxidative reactions and preventing apoptotic death of neurons. In a recent study, Alzheimer’s disease patients taking vitamin E showed a slowing down of cognitive decline15; in experimental studies, a wide variety of antioxidants, including phytochemicals, have shown the ability to prevent oxidative damage.16

Vitamins E and C. Combined treatment with antioxidants has been found to be effective in improving memory in animal studies and in reducing the risk of Alzheimer’s disease dementia. In a study from Brazil, investigators tested homocysteine’s effects in inducing memory impairment in rats and antioxidants’ ability to prevent the deleterious homocysteine effects. Rats pretreated for a week with vitamins C and E were injected with homocysteine before and after being trained to master a task. Memory was severely impaired in the homocysteine-treated group while “treatment with vitamins E and C prevented amnesia.”17

A study of 633 persons aged 65 years and older, with a follow-up period of 4.3 years, found that none of the participants taking vitamin C and E supplements had Alzheimer’s disease at the end of the follow-up period, compared with the predicted incidence of 3.9 observed in non-users of supplements.18

Antioxidant levels decrease with age and are low in people with cognitive impairment.

In a study from the University of Perugia in Italy, investigators measured antioxidant levels in the plasma and cells of 25 elderly patients with mild cognitive impairment, 63 patients with Alzheimer’s disease, and 53 controls. The antioxidants measured were uric acid; vitamins A, E, and C; and carotenoids, including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, and alpha and beta carotene. Also measured were the activities of plasma and red blood cell superoxide dismutase (SOD) and plasma glutathione peroxidase. The findings showed that patients with cognitive impairment and Alzheimer’s disease had low antioxidant levels, compared to control subjects. The study’s authors suggested that as mild cognitive impairment represents an early stage in Alzheimer’s disease and oxidative damage is an early pathological event in dementia, “an increased intake of antioxidants in patients with mild cognitive impairment ”19

Phytochemicals Also Offer Protection
Ginkgo biloba, curcumin, and aged garlic extract are phytochemicals that have been shown to reduce oxidative damage, thus counteracting vascular damage and neurodegeneration.

Ginkgo. Ginkgo biloba supplementation has been shown to improve cognition in people with certain forms of dementia.20 Studies now suggest that some of its protective effects in vascular dementia may be due to reducing oxidative stress and preventing platelet aggregation that give rise to blood clots.

Curcumin. Present in curry, curcumin is a potent antioxidant with anti-inflammatory effects. Studies on an Alzheimer’s disease mouse model show that dietary curcumin reduced oxidative damage and decreased amyloid beta peptides in the brain by 43-50%. In studies on the PC12 neuron cell model, curcumin was more effective than alpha tocopherol in preventing amyloid beta peptide toxicity.21

Aged garlic extract. Garlic contains a wide range of active constituents, which are enhanced by a special process that yields aged garlic extract (Kyolic™).22 Aged garlic extract protects the vascular system by inhibiting platelet aggregation, reducing inflammation, and preventing coronary plaque in humans; aged garlic extract also has neuroprotective effects, reducing homocysteine levels23, preventing amyloid beta peptide toxicity in PC12 neurons,24 and apoptotic death, and improving memory in senility-prone mice.25

In a four-week study at Penn State University, researchers fed rats a folate-deficient diet and Kyolic aged garlic extract, and compared their homocysteine levels to those in rats fed a folate-fortified diet and aged garlic extract. Aged garlic extract reduced plasma homocysteine by 30% in folate-deficient animals, but not at all in animals with adequate folate. The results suggest that aged garlic extract may serve as a surrogate for folate treatment in hyperhomocysteinemia.25

Summary: Lowering Homocysteine Lowers Dementia Risk
Elevated plasma homocysteine (hyperhomocysteinemia) is a major risk factor for dementia, including Alzheimer’s disease. Hyperhomo-cysteinemia commonly results from a deficiency in folate and vitamins B6 and B12, and supplementation with these nutrients is the mainstay preventive and therapeutic treatment for hyperhomocysteinemia. Vegetarians, especially vegans, often have low levels of vitamin B12 and elevated homocysteine, but supplementation with vitamin B12 can return their plasma concentrations to levels of nonvegetarians.

Antioxidant levels decline as a result of normal aging and dementia. Increasing your intake of vitamins C and E—along with phytochemicals such as aged garlic extract, ginkgo biloba, and curcumin that have been shown in experiments to prevent oxidant damage and brain cell death by apoptosis—also may help stave off dementia.


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9. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease: The Nun study. JAMA. 1997 Mar 12;277(10):813-7.

10. Ho PI, Ortiz D, Rogers E, Shea TB. Multiple aspects of homocysteine neurotoxicity gluta mate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res. 2002 Dec 1;70(5):694-702.

11. Kruman II, Kumaravel TS, Lohani A, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. J Neurosci. 2002 Mar 1;22(5):1752-62.

12. Recommended Dietary Allowences (RDA) National Academy Press, Washington DC. 1989 pp 142-164.

13. Leblhuber F, Walli J, Artner-Dworzak E, et al. Homocysteine and B vitamins in dementia.

J Neural Transm. 2000;107(12):1469-74.

14. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holo transcobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.

15. Vatassery GT, Bauer T, Dysken M. et al High doses of vitamin E in the treatment of disor ders of the central nervous system in the aged. Am J Clin Nutr. 1999 Nov;70(5):793-801.

16. Behl C, Moosmann B. Oxidative nerve cell death in Alzheimer’s disease and stroke: antioxidants as neuroprotective com pounds. Biol Chem. 2002 Mar-Apr;383(3- 4):521-36.

17. Reis EA, Zugno AI, Franzon , et al. Pretreatment with vitamins E and C prevent the impairment of memory caused by homo cysteine administration in rats. Metab Brain Dis. 2002 Sep;17(3):211-7.

18. Morris MC, Beckett LA, Scherr PA, et al Vitamin E and Vitamin C supplement use and risk of incident Alzheimer’s disease. Alzheimer Dis Assoc Disord. 1998 Sep;12(3):121-6.

19. Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alz- heimer’s disease. Neurobiol Aging. 2003 Nov;24(7):915-9.

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21. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative stress and amyloid pathol ogy in Alzheimer transgenic mouse. J Neurosci. 2001 Nov 1;21(21):8370-7.

22. Borek C. Antioxidant health effects of aged garlic extract. J Nutr 2001; 131: 1010S-1015S.

23. Yeh YY. Garlic extract reduces plasma con centra tion of homocysteine in rats rendered folic acid deficiency. FASEB 1999; 13: #4 abst 209.1.

24. Brenya G, Selassie M, Gwebie ET. Effect of aged garlic extract on the cytotoxicity of Alzheimer beta amyloid peptide in neuronal PC12 cells. Nutritional Neuroscience 1999;3:139-142.

25. Moriguchi T, Saito H, Nishyama N. Anti- aging effect of aged garlic extract in the inbred brain atrophy mouse model. Clin and Exp. Pharmachol. and Physiol. 1997.24: 235-242.