Objective: To evaluate the association between hyperhomocysteinemia (HHcy) and risk of cognitive decline. Methods: Electronic databases such as PubMed and EMBASE were searched for prospective cohort studies that involved the relationship between HHcy and risk of cognitive decline. Adjusted risk ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were calculated by Review Manager 5.2.7. Subgroup analyses were conducted on stratification of some important variables. Results: Fourteen publications were included in the analysis. The pooled RR was 1.53 (95% CI, 1.23-1.91; p = 0.0002) for patients with HHcy compared to subjects without HHcy. Subgroup analyses indicated that the pooled RRs were 1.51 (95% CI, 1.10-2.05; p = 0.01) for more than five-year follow-up studies and 1. 56 (95% CI, 1.13-2.14; p = 0.007) for less than five-year follow-up studies. The pooled RRs were 1.66 (95% CI, 1.21-2.26; p = 0.001) for studies excluding the confounder of B vitamins and 1.34 (95% CI, 1.08-1.66; p = 0.008) for non-excluded studies. In terms of region, the pooled RR was 1.60 (95% CI, 1.21-2.13; p = 0.001) for European and American countries, while the pooled RR was 1.27 (95% CI, 1.02-1.59; p = 0.03) for other regions. Conclusion: As one of the independent risk factors, HHcy was associated with an increased risk of cognitive decline.

Stead LM, Jacobs RL, Brosnan ME, Brosman JT: Methylation demand and homocysteine metabolism. Adv Enzyme Regul 2004;44:321-333.
Zylberstein DE, Lissner L, Bjorkelund C, Mehlig K, Thelle DS, Gustafson D, Ostling S, Waern M, Guo X, Skoog I: Midlife homocysteine and late-life dementia in women: a prospective population study. Neurobiol Aging 2009;32:380-386.
Nurk E, Refsum H, Tell GS, Engedal K, Vollset SE, Ueland PM, Nygaard HA, Smith AD: Plasma total homocysteine and memory in the elderly: the Hordaland homocysteine study. Ann Neurol 2005;58:847-857.
Whalley LJ, Duthie SJ, Collins AR, Starr JM, Deary IJ, Lemmon H, Duthie AC, Murray AD, Staff RT: Homocysteine, antioxidant micronutrients and late onset dementia. Eur J Nutr 2014;53:277-285.
Kim J, Park MH, Kim E, Han C, Jo SA, Jo I: Plasma homocysteine is associated with the risk of mild cognitive impairment in an elderly Korean population. J Nutr 2007;137:2093-2097.
Kalmijn S, Launer LJ, Lindemans J, Bots ML, Hofman A, Breteler MM: Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol 1999;150:283-289.
Hooshmand B, Solomon A, Kåreholt I, Rusanen M, Hanninen T, Leiviskä J, Winblad B, Laatikainen T, Soininen H, Kivipelto M: Association between serum homocysteine, holo-transcobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 2012;271:204-212.
Ho RCM, Cheung MWL, Fu E, Win HH, Zaw MH, Ng A, Mak A: Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. Am J Geriatr Psychiatry 2011;19:607-617.
Wells G, Shea B, O'Connell D, Peterson J, Welch J, Losos M, Tugwell P: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [EB/OL], 2013, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
Annerbo S, Kivipelto M, Lokk J: A prospective study on the development of Alzheimer's disease with regard to thyroid-stimulating hormone and homocysteine. Dement Geriatr Cogn Disord 2009;28:275-280.
Ravaglia G, Forti P, Maioli F, Chiappelli M, Montesi F, Tumini E, Mariani E, Licastro F, Patterson C: Blood inflammatory markers and risk of dementia: the Conselice Study of Brain Aging. Neurobiol Aging 2007;28:1810-1820.
Reitz C, Tang MX, Miller J, Green R, Luchsinger JA: Plasma homocysteine and risk of mild cognitive impairment. Dement Geriatr Cogn Disord 2009;27:11-17.
Dufouil C, Alperovitch A, Ducros V, Tzourio C: Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol 2003;53:214-221.
Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA: Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-483.
Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R: Plasma homocysteine levels and risk of Alzheimer disease. Neurology 2004;62:1972-1976.
Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F: Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005;82:636-643.
Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, Seeman TE: 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. Am J Med 2005;118:161-167.
Haan MN, Miller JW, Aiello AE, Whitmer RA, Jagust WJ, Mungas DM, Allen LH, Green R: Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2007;85:511-517.
Kivipelto M, Annerbo S, Hultdin J, Backman L, Viitanen M, Fratiglioni L, Lokk J: Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study. Eur J Neurol 2009;16:808-813.
Ford AH, Flicker L, Alfonso H, Hankey GJ, Norman PE, van Bockxmeer FM, Almeida OP: Plasma homocysteine and MTHFRC677T polymorphism as risk factors for incident dementia. J Neurol Neurosurg Psychiatry 2011;83:70-75.
Hendrie HC, Baiyewu O, Lane KA, Purnell C, Gao S, Hake A, Ogunniyi A, Gureje O, Unverzagt FW, Murrell J, Deeg MA, Hall K: Homocysteine levels and dementia risk in Yoruba and African Americans. Int Psychogeriatr 2013;25:1859-1866.
Chen C, Conklin BS, Ren Z, Zhong DS: Homocysteine decreases endothelium-dependent vasorelaxation in porcine arteries. J Surg Res 2002;102:22-30.
Vuckovic BA, Cabarkapa VS, Ilic TA, Salatic IR, Lozanov-Crvenkovic ZS, Mitic GP: Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients. Croat Med J 2013;54:480-488.
Herrmann W, Herrmann M, Obeid R: Hyperhomocysteinaemia: a critical review of old and new aspects. Curr Drug Metab 2007;8:17-31.
Kuszczyk M, Gordon-Krajcer W, Lazarewicz JW: Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau. Neurochem Int 2009;55:174-180.
Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H: Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One 2010;5:e12244.
Connelly PJ, Prentice NP, Cousland G, Bonham J: A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry 2008;23:155-160.
Thompson SG: Why sources of heterogeneity in meta-analysis should be investigated. BMJ 1994;309:1351-1355.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.