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 Feb;118(2):161-7. doi: 10.1016/j.amjmed.2004.08.019.


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 B(6), and vitamin B(12) 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 B(6), 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aging / psychology*
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / physiopathology
  • Cognition Disorders / etiology*
  • Cognition Disorders / physiopathology
  • Cohort Studies
  • Cross-Sectional Studies
  • Female
  • Folic Acid / blood*
  • Folic Acid Deficiency / complications
  • Homocysteine / blood*
  • Humans
  • Longitudinal Studies
  • Male
  • Risk Factors
  • Vitamin B 12 / blood*
  • Vitamin B 6 / blood*


  • Homocysteine
  • Vitamin B 6
  • Folic Acid
  • Vitamin B 12