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

Deborah M. Kado*, Arun S. Karlamangla, Mei Hua Huang, Aron Troen, John W. Rowe, Jacob Selhub, Teresa E. Seeman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

235 Scopus citations


Background: Elevated plasma total homocysteine concentration may be a risk factor for cognitive decline and Alzheimer disease, but data from prospective studies are limited. Further, high homocysteine levels are associated with low vitamin status, and it is unknown whether it is homocysteine toxicity or vitamin insufficiency that is responsible for the observed cognitive dysfunction. Methods: We performed cross-sectional and longitudinal analyses of a cohort of 499 high-functioning community-dwelling persons aged 70 to 79 years to determine the effect of homocysteine and related vitamin plasma concentrations on cognitive function and cognitive decline. Nonfasting plasma concentrations of homocysteine, folate, vitamin B6, and vitamin B12 were measured at baseline. Summary measures of cognitive function were created from tests of multiple cognitive domains administered at baseline and again after 7 years. Results: In cross-sectional analyses investigating each variable separately, subjects with elevated homocysteine levels, or low levels of folate or vitamin B6, demonstrated worse baseline cognitive function. In longitudinal analyses, after adjusting for multiple covariates, including homocysteine, those in the bottom quartile of folate had a 1.6-fold increased risk (95% confidence interval: 1.01 to 2.31; P =0.04) of being in the worst quartile of 7-year cognitive decline. Low folate levels largely accounted for a trend towards greater cognitive decline with elevated homocysteine level. Conclusion: In high-functioning older adults, low folate levels appear to be a risk factor for cognitive decline. The risk of developing cognitive decline might be reduced through dietary folate intake.

Original languageAmerican English
Pages (from-to)161-167
Number of pages7
JournalAmerican Journal of Medicine
Issue number2
StatePublished - Feb 2005
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by NIH/NIA Grants AG-00586, AG-17056, AG-17265, and 1K12AG01004, and the MacArthur Research Network on Successful Aging through grants from the John D. and Catherine T. MacArthur Foundation. This project was also supported by the U.S. Department of Agriculture under cooperative agreement No. 58-1950-9-001. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the MacArthur Foundation or the U.S. Department of Agriculture.


  • Aging
  • Cognitive decline
  • Cognitive impairment
  • Folate
  • Homocysteine
  • Vitamin B
  • Vitamin B


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