February 2002
Sudha Seshadri, M.D., Alexa Beiser, Ph.D., Jacob Selhub, Ph.D., Paul F. Jacques, Sc.D., Irwin H. Rosenberg, M.D., Ralph B. D'Agostino, Ph.D., Peter W.F. Wilson, M.D., and Philip A. Wolf, M.D.

 

Abstract

BACKGROUND

In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies.

 

METHODS

A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6.

 

RESULTS

Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 μmol per liter, the risk of Alzheimer's disease nearly doubled.

 

CONCLUSIONS

An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

 

Alzheimer's disease accounts for more than 70 percent of all cases of dementia, so it is important to identify modifiable risk factors for the disease.1 During the past decade, there has been growing interest in vascular factors that may underlie Alzheimer's disease. It is now recognized that subjects with cardiovascular risk factors and a history of stroke have an increased risk of both vascular dementia and Alzheimer's disease.2-4 Plasma total homocysteine has recently emerged as a major vascular risk factor. Elevated total homocysteine levels have been associated with an increased risk of atherosclerotic sequelae, including death from cardiovascular causes,5,6 coronary heart disease,6,7 carotid atherosclerosis,8 and clinical stroke.9,10 These observations led to the hypothesis that elevated plasma homocysteine may be a risk factor for dementia and Alzheimer's disease. If this hypothesis is valid, it points to a modifiable risk factor, since plasma homocysteine levels can be lowered by supplementation with folic acid.11

Previous studies have reported an inverse association between plasma total homocysteine levels and simultaneously assessed cognitive function.12-16 Two case–control studies have found higher plasma homocysteine levels in persons with Alzheimer's disease.17,18 However, in a prospective study plasma homocysteine levels were not related to cognitive decline during follow-up in a community-based sample.19 Elevated plasma homocysteine levels in subjects with cognitive impairment or dementia might be the result of poor nutrition and vitamin deficiencies.20 A prospective study should be able to show whether elevated plasma homocysteine in cognitively intact adults is associated with an increased risk of dementia and Alzheimer's disease on follow-up. We therefore examined plasma total homocysteine in relation to newly diagnosed dementia and Alzheimer's disease in the elderly, population-based cohort of Framingham Study participants.