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B-vitamins and prevention of dementia: Plenary Lecture

  • Robert Clarke (a1)

Elevated plasma homocysteine (Hcy) concentrations have been implicated with risk of cognitive impairment and dementia, but it is unclear whether low vitamin B12 or folate status is responsible for cognitive decline. Most studies reporting associations between cognitive function and Hcy or B-vitamins have used a cross-sectional or case–control design and have been unable to exclude the possibility that such associations are a result of the disease rather than being causal. The Hcy hypothesis of dementia has attracted considerable interest, as Hcy can be easily lowered by folic acid and vitamin B12, raising the prospect that B-vitamin supplementation could lower the risk of dementia. While some trials assessing effects on cognitive function have used folic acid alone, vitamin B12 alone or a combination, few trials have included a sufficient number of participants to provide reliable evidence. An individual-patient-data meta-analysis of all randomised trials of the effects on cognitive function and vascular risk of lowering Hcy with B-vitamins will maximise the power to assess the epidemiologically-predicted differences in risk. Among the twelve large randomised Hcy-lowering trials for prevention of vascular disease, data should be available on about 30 000 participants with cognitive function. The principal investigators of such trials have agreed to combine individual-participant data from their trials after their separate publication.

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Corresponding author
Corresponding author: Dr Robert Clarke, fax +44 1865 743985, email
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1. Clarke, R, Smith, AD, Jobst, KA, Refsum, H, Sutton, L & Ueland, PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55, 14491455.
2. Clarke, R (2006) Vitamin B12, folic acid, and the prevention of dementia. N Engl J Med 354, 28172819.
3. Homocysteine-Lowering Trialists' Collaboration (2005) Dose-dependent effects of folic acid on plasma homocysteine concentrations. A meta-analysis of the randomised trials. Am J Clin Nutr 82, 806812.
4. Joosten, E, Lesaffre, E, Riezler, R, Ghekiere, V, Dereymaeker, L, Pelemans, W & Dejaeger, E (1997) Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer's disease? J Gerontol A Biol Sci Med Sci 52, 7679.
5. McCaddon, A, Davies, G, Hudson, P, Tandy, S & Cattell, H (1998) Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry 13, 235239.
6. Riggs, KM, Spiro, A 3rd, Tucker, K & Rush, D (1996) Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 63, 306314.
7. McCaddon, A, Hudson, P, Davies, G, Hughes, A, Williams, JH & Wilkinson, C (2001) Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 12, 309313.
8. Morris, MS, Jacques, PF, Rosenberg, IH & Selhub, J (2001) Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 73, 927933.
9. Duthie, SJ, Whalley, LJ, Collins, AR, Leaper, S, Berger, K & Deary, IJ (2002) Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 75, 908913.
10. Budge, M, Johnston, C, Hogervorst, E, de Jager, C, Milwain, E, Iversen, SD, Barnetson, L, King, E & Smith, AD (2000) Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann N Y Acad Sci 903, 407410.
11. Tucker, KL, Qiao, N, Scott, T, Rosenberg, I & Spiro, A 3rd (2005) High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr 82, 627635.
12. Kado, DM, Bucur, A, Selhub, J, Rowe, JW & Seeman, T (2002) Homocysteine levels and decline in physical function: MacArthur Studies of Successful Aging. Am J Med 113, 537542.
13. Mooijaart, SP, Gussekloo, J, Frolich, M, Jolles, J, Stott, DJ, Westendorp, RG & de Craen, AJ (2005) Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr 82, 866871.
14. Nurk, E, Refsum, H, Tell, GS, Engedal, K, Vollset, SE, Ueland, PM, Nygaard, HA & Smith, AD (2005) Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 58, 847857.
15. Prins, ND, Den Heijer, T, van Dijk, EJ, Jolles, J, Koudestall, PJ, Hofman, A, Clarke, R & Breteler, MMB (2006) Homocysteine and cognitive function in the elderly: The Rotterdam study. Neurology 59, 13751380.
16. Seshadri, S, Beiser, A, Selhub, J, Jacques, PF, Rosenberg, IH, D'Agostino, RB, Wilson, PW & Wolf, PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346, 476483.
17. Ravaglia, G, Forti, P, Maioli, F, Martelli, M, Servadei, L, Brunetti, N, Porcellini, E & Licastro, F (2005) Homocysteine and folate as risk factors for dementia and Alzheimer's disease. Am J Clin Nutr 82, 636643.
18. Luchsinger, JA, Tang, MX, Shea, S, Miller, J, Green, R & Mayeux, R (2004) Plasma homocysteine levels and risk of Alzheimer disease. Neurology 62, 19721976.
19. Clarke, R, Refsum, H, Birks, J et al. (2003) Screening for vitamin B12 and folate deficiency in older people. Am J Clin Nutr 77, 12411247.
20. Morris, MC, Evans, DA, Bienias, JL, Tangney, CC, Hebert, LE, Scherr, PA & Schneider, JA (2005) Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 62, 641645.
21. Morris, MS, Jacques, PF, Rosenberg, IW & Selhub, J (2007) Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85, 193200.
22. Lindenbaum, J, Healton, EB, Savage, DG, Brust, JC, Garrett, TJ, Podell, ER, Marcell, PD, Stabler, SP & Allen, RH (1988) Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318, 17201728.
23. Smulders, YM & Stehouwer, CDA (2005) Folate metabolism and cardiovascular disease. Seminars Vasc Med 5, 8797.
24. Schneede, J & Ueland, PM (2005) Novel and established markers of cobalamin deficiency: complimentary or exclusive diagnostic strategies. Seminars Vasc Med 5, 140155.
25. Clarke, R, Grimley Evans, J, Schneede, J et al. (2004) Vitamin B12 and folate deficiency in older people. Age Ageing 33, 3441.
26. Hin, H, Clarke, R, Sherliker, P et al. (2006) Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Ageing 35, 416422.
27. Clarke, R, Sherliker, S, Hin, H et al. (2007) Detection of vitamin B12 deficiency in older people by measuring vitamin B12, or the active fraction of vitamin B12, holotranscobalamin. Clin Chem 53, 963–970.
28. Cummings, JL (2004) Alzheimer's disease. N Engl J Med 351, 5667.
29. Vermeer, SE, van Dijk, EJ, Koudstaal, PJ et al. (2002) Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurology 51, 285290.
30. den Heijer, T, Vermeer, SE, Clarke, R et al. (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126, 170175.
31. Department of Health (2006) Folate and Disease Prevention. London: The Stationery Office.
32. Mills, JL, Von Kohorn, I, Conley, MR et al. (2003) Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 77, 14741477.
33. Metz, J, McNeil, AR & Levin, M (2004) The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate. Clin Lab Haematol 26, 323325.
34. Dhar, M, Bellevue, R & Carmel, R (2003) Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. N Engl J Med 348, 22042207.
35. Pfeiffer, CM, Caudill, SP, Gunter, EW, Osterloh, J & Sampson, EJ (2005) Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr 82, 442450.
36. B-Vitamin Treatment Trialists' Collaboration (2006) Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 151, 282287.
37. Durga, J, van Boxtel, MP, Schouten, EG, Kok, FJ, Jolles, J, Katan, MB & Verhoef, P (2007) Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 369, 208216.
38. Balk, EM, Raman, G, Tatsioni, A, Chung, M, Lau, J & Rosenberg, IW (2007) Vitamin B6, B12 and folic acid supplementation and cognitive function: a systematic review of randomized trials. Arch Intern Med 167, 2130.
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Proceedings of the Nutrition Society
  • ISSN: 0029-6651
  • EISSN: 1475-2719
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