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Cognitive impairment and vitamin B12: a review

  • Eileen Moore (a1), Alastair Mander (a2), David Ames (a3), Ross Carne (a4), Kerrie Sanders (a5) and David Watters (a6)...


Background: This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia.

Methods: A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions.

Results: Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimer's disease, vascular dementia, and Parkinson's disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 ρmol/L or serum homocysteine levels >19.9 μmol/L).

Conclusion: Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease.


Corresponding author

Correspondence should be addressed to: Eileen Mary Moore, Department of Surgery, Barwon Health, The Geelong Hospital, PO Box 281, Geelong, Victoria 3220, Australia. Phone: +61 352267899; Fax: +61 352267019. Email:,


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Aaron, S., Kumar, S., Vijayan, J., Jacob, J., Alexander, M. and Gnanamuthu, C. (2005). Clinical and laboratory features and response to treatment in patients presenting with vitamin B12 deficiency-related neurological syndromes. Neurology India, 53, 5559.
Abyad, A. (2002). Prevalence of vitamin B12 deficiency among demented patients and cognitive recovery with cobalamin replacement. Journal of Nutrition, Health and Aging, 6, 254260.
Adams, J. F., Clark, J. S., Ireland, J. T., Kesson, C. M. and Watson, W. S. (1983). Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia, 24, 1618.
Aisen, P. S. et al. (2008). High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA, 300, 17741783. doi: 10.1001/jama.300.15.1774.
Akdal, G., Yener, G. G. and Kurt, P. (2008). Treatment responsive executive and behavioral dysfunction associated with vitamin B12 deficiency. Neurocase, 14, 147150. doi: 10.1080/13554790802032242.
Alzheimer's Association (2011). 2011 Alzheimer's disease – facts and figures. Alzheimer's and Dementia, 7, 208244.
Ames, D., Burns, A. and O'Brien, J. (2010). Dementia, 4th edn. London: Edward Arnold (Publishers) Limited.
Andres, E. et al. (2004). Vitamin B12 (cobalamin) deficiency in elderly patients. Canadian Medical Association Journal, 171, 251259. doi: 10.1503/cmaj.1031155.
Annerbo, S., Kivipelto, M. and Lokk, J. (2009). A prospective study on the development of Alzheimer's disease with regard to thyroid-stimulating hormone and homocysteine. Dementia and Geriatric Cognitive Disorders, 28, 275280. doi: 10.1159/000242439.
Bauman, W. A., Shaw, S., Jayatilleke, E., Spungen, A. M. and Herbert, V. (2000). Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care, 23, 12271231.
Bell, D. S. (2010). Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy. Southern Medical Journal, 103, 265267.
Brady, C. B. et al. (2009). Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study. American Journal of Kidney Diseases, 54, 440449. doi: 10.1053/j.ajkd.2009.05.013.
Brewerton, D. A. and Asher, R. A. (1952). The maintenance therapy of pernicious anaemia with vitamin B12. Lancet, 6728, 265266.
Chen, Y. et al. (2009). Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proceedings of the National Academy of Sciences of the United States of America, 106, 39073912. doi: 10.1073/pnas.0807991106.
Clarfield, A. M. (2003). The decreasing prevalence of reversible dementias: an updated meta-analysis. Archives of Internal Medicine, 163, 22192229.
Clarke, R., Smith, A. D., Jobst, K. A., Refsum, H., Sutton, L. and Ueland, P. M. (1998). Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology, 55, 14491455.
Clarke, R. et al. (2007). Low vitamin B-12 status and risk of cognitive decline in older adults. American Journal of Clinical Nutrition, 86, 13841391.
Cunha, U. G. et al. (1995). Vitamin B12 deficiency and dementia. International Psychogeriatrics, 7, 8588.
de Lau, L. M. L., Smith, A. D., Refsum, H., Johnston, C. and Breteler, M. M. B. (2009). Plasma vitamin B12 status and cerebral white-matter lesions. Journal of Neurology, Neurosurgery and Psychiatry, 80, 149157. doi: 10.1136/jnnp.2008.149286.
Di Carlo, A. et al. (2002). Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA study. Journal of the American Geriatrics Society, 50, 4148.
Dogan, M. et al. (2009). Psychotic disorder and extrapyramidal symptoms associated with vitamin B12 and folate deficiency. Journal of Tropical Pediatrics, 55, 205207. doi: 10.1093/tropej/fmn112.
Elias, M. F. et al. (2005). Homocysteine and cognitive performance in the Framingham offspring study: age is important. American Journal of Epidemiology, 7, 644653. doi: 10.1093/aje/kwi259.
Elias, M. F. et al. (2006). Homocysteine, folate, and vitamins B6 and B12 blood levels in relation to cognitive performance: the Maine–Syracuse study. Psychosomatic Medicine, 68, 547554. doi: 10.1097/01.psy.0000221380.92521.51.
Eussen, S. J. et al. (2006). Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. American Journal of Clinical Nutrition, 84, 361370.
Ferri, C. P. et al. (2005). Global prevalence of dementia: a Delphi consensus study. Lancet, 9503, 21122117.
Figlin, E. et al. (2003). High prevalences of vitamin B12 and folic acid deficiency in elderly subjects in Israel. British Journal of Haematology, 123, 696701.
Folstein, M. F., Folstein, S. E. and McHugh, P. R. (1975). “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189198.
Gadoth, N., Figlin, E., Chetrit, A., Sela, B. A. and Seligsohn, U. (2006). The neurology of cobalamin deficiency in an elderly population in Israel. Journal of Neurology, 253, 4550. doi: 10.1007/s00415-005-0919-4.
Garcia, A., Paris-Pombo, A., Evans, L., Day, A. and Freedman, M. (2002). Is low-dose oral cobalamin enough to normalize cobalamin function in older people? Journal of the American Geriatrics Society, 50, 14011404.
Gochard, A., Mondon, K., De Toffol, B. and Autret, A. (2009). Vitamin B12 deficiency and neurological disorders: a case report and literature review. Revue Neurologique, 165, 10951098.
Gorgone, G. et al. (2009). Hyperhomocysteinemia in patients with epilepsy: does it play a role in the pathogenesis of brain atrophy? A preliminary report. Epilepsia, 50, 3336. doi: 10.1111/j.1528-1167.2008.01967.x.
Herbert, V. (1988). Vitamin B-12: plant sources, requirements, and assay. American Journal of Clinical Nutrition, 48, 852858.
Herbert, V. (1994). Staging vitamin B-12 (cobalamin) status in vegetarians. American Journal of Clinical Nutrition, 59, 1213S1222S.
Hin, H. et al. (2006). Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age and Ageing, 35, 416422. doi:10.1093/ageing/afl033.
Hokin, B. D. and Butler, T. (1999). Cyanocobalamin (vitamin B-12) status in Seventh-Day Adventist ministers in Australia. American Journal of Clinical Nutrition, 70, 576578.
Huemer, M. et al. (2006). Total homocysteine, folate, and cobalamin, and their relation to genetic polymorphisms, lifestyle and body mass index in healthy children and adolescents. Pediatric Research, 60, 764769. doi: 10.1203/01.pdr.0000246099.39469.18.
Hvas, A. M., Juul, S., Lauritzen, L., Nexo, E. and Ellegaard, J. (2004). No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. Journal of Affective Disorders, 81, 269273. doi: 10.1016/S0165-0327(03)00169-1.
Jorm, A. F., Korten, A. E. and Henderson, A. S. (1987). The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatrica Scandinavica, 76, 465479.
Josephs, K. A. et al. (2009). Rapidly progressive neurodegenerative dementias. Archives of Neurology, 66, 201207.
Kado, D. M. et al. (2005). Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur studies of successful aging. American Journal of Medicine, 118, 161167. doi:10.1016/j.amjmed.2004.08.019.
Kalita, J. and Misra, U. K. (2008). Vitamin B12 deficiency neurological syndromes: correlation of clinical, MRI and cognitive evoked potential. Journal of Neurology, 255, 353359. doi: 10.1007/s00415-008-0660-x.
Kaptan, K. et al. (2000). Helicobacter pylori – is it a novel causative agent in vitamin B12 deficiency? Archives of Internal Medicine, 160, 13491353.
Kim, J. M. et al. (2008a). Changes in folate, vitamin B12 and homocysteine associated with incident dementia. Journal of Neurology, Neurosurgery and Psychiatry, 79, 864868. doi: 10.1136/jnnp.2007.131482.
Kim, J. M., Stewart, R., Kim, S. W., Yang, S. J., Shin, I. S. and Yoon, J. S. (2008b). Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. British Journal of Psychiatry, 192, 268274. doi: 10.1192/bjp.bp.107.039511.
Koseoglu, E. and Karaman, Y. (2007). Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clinical Biochemistry, 40, 859863. doi:10.1016/j.clinbiochem.2007.04.007.
Kuo, S. C., Yeh, C. B., Yeh, Y. W. and Tzeng, N. S. (2009). Schizophrenia-like psychotic episode precipitated by cobalamin deficiency. General Hospital Psychiatry, 31, 586588. doi: 10.1016/j.genhosppsych.2009.02.003.
Kwok, T., Lee, J., Lam, L. and Woo, J. (2008). Vitamin B(12) supplementation did not improve cognition but reduced delirium in demented patients with vitamin B(12) deficiency. Archives of Gerontology and Geriatrics, 46, 273282. doi: 10.1016/j.archger.2007.05.001.
Lanska, D. J. (2009). Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. Handbook of Clinical Neurology, 95, 445476.
Lehmann, M., Regland, B., Blennow, K. and Gottfries, C. G. (2003). Vitamin B12-B6-folate treatment improves blood–brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment. Dementia and Geriatric Cognitive Disorders, 16, 145150. doi: 10.1159/000071002.
Lipton, S. A. et al. (1997). Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proceedings of the National Academy of Sciences of the United States of America, 94, 59235928.
Loikas, S. et al. (2007). Vitamin B12 deficiency in the aged: a population-based study. Age and Ageing, 36, 177183. doi: 10.1093/ageing/afl150.
Malaguarnera, M., Ferri, R., Bella, R., Alagona, G., Carnemolla, A. and Pennisi, G. (2004). Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clinical Chemisty and Laboratory Medicine, 42, 10321035. doi: 10.1515/CCLM.2004.208.
Martin, D. C., Francis, J., Protetch, J. and Huff, F. J. (1992). Time dependency of cognitive recovery with cobalamin replacement: report of a pilot study. Journal of the American Geriatrics Society, 40, 168172.
McLean, E., de Benoist, B. and Allen, L. H. (2008). Review of the magnitude of folate and vitamin B12 deficiencies worldwide. Food and Nutrition Bulletin, 29, 3851.
McMahon, J. A., Green, T. J., Skeaff, C. M., Knight, R. G., Mann, J. I. and Williams, S. M. (2006). A controlled trial of homocysteine lowering and cognitive performance. The New England Journal of Medicine, 354, 27642772.
Miller, J. W., Garrod, M. G., Allen, L. H., Haan, M. N. and Green, R. (2009). Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate. American Journal of Clinical Nutrition, 90, 15861592.
Myles, P. S., Chan, M. T., Leslie, K., Peyton, P., Paech, M. and Forbes, A. (2008). Effect of nitrous oxide on plasma homocysteine and folate in patients undergoing major surgery. British Journal of Anaesthesia, 100, 780786. doi: 10.1093/bja/aen085.
Nilsson, K., Gustafson, L. and Hultberg, B. (2001). Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. International Journal of Geriatric Psychiatry, 16, 609614. doi: 10.1002/gps.388.
Okun, J. G. et al. (2002). Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity. Journal of Biological Chemistry, 277, 1467414680. doi: 10.1074/jbc.M200997200.
Oostenbrug, L. E., van Dullemen, H. M., te Meerman, G. J., Jansen, P. L. and Kleibeuker, J. H. (2006). Clinical outcome of Crohn's disease according to the Vienna classification: disease location is a useful predictor of disease course. European Journal of Gastroenterology and Hepatology, 18, 255261.
Pasca, S. P. et al. (2008). One carbon metabolism disturbances and the C667T MTHFR gene polymorphism in children with autism spectrum disorders. Journal of Cellular and Molecular Medicine, 13, 42294238. doi:10.1111/j.1582-4934.2008.00463.x.
Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G. and Kokmen, E. (1999). Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology, 56, 303308.
Pfeiffer, C. M., Caudill, S. P., Gunter, E. W., Osterloh, J. and Sampson, E. J. (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. American Journal of Clinical Nutrition, 82, 442450.
Profenno, L. A., Porsteinsson, A. P. and Faraone, S. V. (2009). Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biological Psychiatry, 67, 505512. doi: 10.1016/j.biopsych.2009.02.013.
Puntambekar, P., Basha, M. M., Zak, I. T. and Madhavan, R. (2009). Rare sensory and autonomic disturbances associated with vitamin B12 deficiency. Journal of Neurological Sciences, 287, 285287. doi:10.1016/j.jns.2009.07.030.
Ravaglia, G. et al. (2003). Homocysteine and cognitive function in healthy elderly community elderly in Italy. American Journal of Clinical Nutrition, 77, 668673.
Ray, J. G., Goodman, J., O'Mahoney, P. R., Mamdani, M. M. and Jiang, D. (2008). High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. Quarterly Journal of Medicine, 101, 475477. doi: 10.1093/qjmed/hcn031.
Redeen, S., Ryberg, A., Petersson, F., Eriksson, O., Nagga, K. and Borch, K. (2009). Homocysteine levels in chronic gastritis and other conditions: relations to incident cardiovascular disease and dementia. Digestive Diseases and Sciences, 55, 351358. doi: 10.1007/s10620-009-0761-0.
Seal, E. C., Metz, J., Flicker, L. and Melny, J. (2002). A randomized, double-blind, placebo-controlled study of oral vitamin B12 supplementation in older patients with subnormal or borderline serum vitamin B12 concentrations. Journal of the American Geriatric Society, 50, 146151.
Selhub, J., Morris, M. S., Jacques, P. F. and Rosenberg, I. H. (2009). Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. American Journal of Clinical Nutrition, 89, 702706.
Serot, J. M. et al. (2005). Homocysteine and methylmalonic acid concentrations in cerebrospinal fluid: relation with age and Alzheimer's disease. Journal of Neurology, Neurosurgery and Psychiatry, 76, 15851587. doi: 10.1136/jnnp.2004.056119.
Siuda, J. et al. (2009). From mild cognitive impairment to Alzheimer's disease – influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up. Polish Journal of Nuerology and Neurosurgery, 43, 321329.
Stott, D. J. et al. (2005). Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. American Journal of Clinical Nutrition, 82, 13201326.
Stuerenburg, H. J., Mueller-Thomsen, T. and Methner, A. (2004). Vitamin B12 plasma concentrations in Alzheimer disease. Neuroendocrinology Letters, 25, 176177.
Tanaka, T. et al. (2009). Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. American Journal of Human Genetics, 84, 477482. doi: 10.1016/j.ajhg.2009.02.011.
Tomkin, G. H. (1972). Metformin and B12 malabsorption. Annals of Internal Medicine, 76, 668.
Triantafyllou, N. I. et al. (2008). Folate and vitamin B12 levels in levodopa-treated Parkinson's disease patients: their relationship to clinical manifestations, mood and cognition. Parkinsonism and Related Disorders, 14, 321325. doi: 10.1016/j.parkreldis.2007.10.002.
van Asselt, D. Z. et al. (1998). Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects. American Journal of Clinical Nutrition, 68, 328334.
van Asselt, D. Z. et al. (2001). Cobalamin supplementation improves cognitive and cerebral function in older, cobalamin-deficient persons. The Journal of Gerontology, Series A, Biological Sciences and Medical Sciences, 56, 775779.
van Uffelen, J. G., Chinapaw, M. J., van Mechelen, W. and Hopman-Rock, M. (2008). Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. British Journal of Sports Medicine, 42, 344351. doi: 10.1136/bjsm.2007.044735.
Vogiatzoglou, et al. (2008). Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 71, 826832.
Wang, H. X., Wahlin, A., Basun, H., Fastbom, J., Winblad, B. and Fratiglioni, L. (2001). Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology, 56, 11881194.
Wang, Y. H. et al. (2009). An investigation of vitamin B12 deficiency in elderly inpatients in neurology department. Neuroscience Bulletin, 25, 209215. doi: 10.1007/s12264-009-0224-9.
Whyte, E. M. et al. (2002). Cognitive and behavioral correlates of low vitamin B12 levels in elderly patients with progressive dementia. American Journal of Geriatric Psychiatry, 10, 321327.
Wile, D. J. and Toth, C. (2010). Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care, 33, 156161. doi: 10.2337/dc09-0606.
Willem, M. et al. (2006). Control of peripheral nerve myelination by the beta-secretase BACE1. Science, 314, 664666. doi: 10.1126/science.1132341.
Wimo, A. and Prince, M. (2010). World Alzheimer Report 2010 – The Global Economic Impact of Dementia. Stockholm: Karolinska Institutet.
Wright, C. B., Lee, H. S., Paik, M. C, Stabler, S. P., Allen, R. H. and Sacco, R. L. (2004). Total homocysteine and cognition in a tri-ethnic cohort: the northern Manhattan study. Neurology, 27, 254260.


Cognitive impairment and vitamin B12: a review

  • Eileen Moore (a1), Alastair Mander (a2), David Ames (a3), Ross Carne (a4), Kerrie Sanders (a5) and David Watters (a6)...


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