Skip to main content

Plasma homocysteine and cognitive decline in older hypertensive subjects

  • Sunil K. Narayan (a1), Brian K. Saxby (a1), Michael J. Firbank (a1), John T. O'Brien (a1), Frances Harrington (a1), Ian G. McKeith (a1), Monica Hansrani (a2), Gerard Stansby (a3) and Gary A. Ford (a1)...

Background: Elevated plasma homocysteine concentrations have been associated with both cognitive impairment and dementia. However, it is unclear whether some cognitive domains are more affected than others, or if this relationship is independent of B12 and folate levels, which can also affect cognition. We examined the relationship between plasma homocysteine and cognitive decline in an older hypertensive population.

Methods: 182 older people (mean age 80 years) with hypertension and without dementia, were studied at one center participating in the Study on COgnition and Prognosis in the Elderly (SCOPE). Annual cognitive assessments were performed using a computerized assessment battery and executive function tests, over a 3–5 year period (mean 44 months). Individual rates of decline on five cognitive domains were calculated for each patient. End of study plasma homocysteine, folate and B12 concentrations were measured. The relationship between homocysteine levels and cognitive decline was studied using multivariate regression models, and by comparing high versus low homocysteine quartile groups.

Results: Higher homocysteine showed an independent association with greater cognitive decline in three domains: speed of cognition (β = −27.33, p = 0.001), episodic memory (β = −1.25, p = 0.02) and executive function (β = −0.05, p = 0.04). The association with executive function was no longer significant after inclusion of folate in the regression model (β = −0.032, p = 0.22). Change in working memory and attention were not associated with plasma homocysteine, folate or B12. High homocysteine was associated with greater decline with a Cohen's d effect size of approximately 0.7 compared to low homocysteine.

Conclusions: In a population of older hypertensive patients, higher plasma homocysteine was associated with cognitive decline.

Corresponding author
Correspondence should be addressed to: Professor Gary A. Ford, Level 6 Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. Phone: +44–191-222-7744; Fax: +44-191-282-0288. Email:
Hide All
Budge M. M., De Jager C. A., Hogervorst E., Smith A. D. and Oxford Project to Investigate Memory and Ageing (Optima) (2002). Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people. Journal of the American Geriatrics Society, 50, 20142018.
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.
Durga J. et al. (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.
Elias M. F. et al. (2005). Homocysteine and cognitive performance in the Framingham Offspring Study: age is important. American Journal of Epidemiology, 162, 644653.
Feng L., Ng T. P., Chuah L., Niti M. and Kua E. H. (2006). Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. American Journal of Clinical Nutrition, 84, 15061512.
Folstein M., Folstein S. and McHugh P. (1975). “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinican. Journal of Psychiatric Research, 12, 189198.
Ford A. H. et al. (2010). Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology, 75, 15401547.
Garcia A., Haron Y., Pulman K., Hua L. and Freedman M. (2004). Increases in homocysteine are related to worsening of stroop scores in healthy elderly persons: a prospective follow-up study. Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 59, 13231327.
Hansson L. et al. (1999). Study on COgnition and Prognosis in the Elderly (SCOPE). Blood Pressure, 8, 177183.
Homocysteine Studies Collaboration (2002). Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA, 288, 20152022.
Hooshmand B. et al. (2010). Homocysteine and holotranscobalamin and the risk of Alzheimer Disease: a longitudinal study. Neurology, 75, 14081414.
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. Amercian Journal of Medicine, 118, 161167.
Kalmijn S., Launer L. J., Lindemans J., Bots M. L., Hofman A. and Breteler M. M. (1999). Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. The American Journal of Epidemiology, 150, 283289.
Lonati S. et al. (2004). Analytical performance and method comparison study of the total homocysteine fluorescence polarization immunoassay (FPIA) on the AxSYM analyzer. Clinical Chemistry and Laboratory Medicine, 42, 228234.
McCaddon A. and Regland B. (2006). Homocysteine and cognition: no longer a hypothesis? Medical Hypotheses, 66, 682683.
Mooijaart S. P. et al. (2005). Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. American Journal of Clinical Nutrition, 82, 866871.
Muda P. et al. (2005). Effect of antihypertensive treatment with candesartan or amlodipine on glutathione and its redox status, homocysteine and vitamin concentrations in patients with essential hypertension. Journal of Hypertension, 23, 105112.
Nelson H. E. and O'Connell A. (1978). Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex, 14, 234244.
Nurk E. et al. (2005). Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Annals of Neurology, 58, 847857.
ONTARGET Investigators et al. (2008). Telmisartan, ramipril, or both in patients at high risk for vascular events. New England Journal of Medicine, 358, 15471559. doi: 10.1056/NEJMoa0801317.
Prins N. D. et al. (2002). Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology, 59, 13751380.
Reitan R. (1958). Validity of the trailmaking test as an indicator of organic brain damage. Perceptual Motor Skills, 8, 271276.
Saxby B. K., Harrington F., Mckeith I. G., Wesnes K. A. and Ford G. A. (2003). Effects of hypertension on attention, memory, and executive function in older adults. Health Psychology, 22, 587591.
Saxby B. K., Harrington F., Wesnes K. A., Mckeith I. G. and Ford G. A. (2008). Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology, 70, 18581866.
Schafer J. H., Glass T. A., Bolla K. I., Mintz M., Jedlicka A. E. and Schwartz B. S. (2005). Homocysteine and cognitive function in a population-based study of older adults. Journal of the American Geriatrics Society, 53, 381388.
Seshadri S. (2006). Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer's disease? Journal of Alzheimer's Disease, 9, 393398.
Seshadri S. et al. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. New England Journal of Medicine, 346, 476483.
Simpson P., Surmon D., Wesnes K. A. and Wilcock G. (1991). The Cognitive Drug Research computerized assessment system for demented patients: a validation study. International Journal of Geriatric Psychiatry, 6, 95102.
Smith A. D. et al. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE, 5, e12244. doi: 10.1371/journal.pone.0012244.
Spreen O. and Strauss E. (1997). A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. New York: Oxford University Press.
Troen A. M. (2005). The central nervous system in animal models in hyperhomocysteinemia. Progress in Neuro-Pyschopharmacology and Biological Psychiatry, 29, 11401151.
Tucker K. L., Qiao N., Scott T., Rosenberg I. H. and Spiro Iii A. (2005). High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. American Journal of Clinical Nutrition, 82, 627635.
van Dam F. and van Gool W. A. (2009). Hyperhomocysteinemia and Alzheimer's disease: a systematic review. Archives of Gerontology and Geriatrics, 48, 425430.
Wilson D. H. et al. (1995). Ion capture assay for folate with the Abbott IMx analyzer. Clinical Chemistry, 41, 17801781.
Wilson D. H., Yu J., Karian A., Kozlowski J. and O'Reilly S. (1999). Development and multisite evaluation of an automated assay for B12 on the Abbott AxSYM analyzer. Clinical Chemistry, 45, 428429.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

International Psychogeriatrics
  • ISSN: 1041-6102
  • EISSN: 1741-203X
  • URL: /core/journals/international-psychogeriatrics
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 1
Total number of PDF views: 11 *
Loading metrics...

Abstract views

Total abstract views: 161 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th November 2017. This data will be updated every 24 hours.