N Engl J Med 2002; 346(7):476-483
Seshadri,S.; Beiser,A.; Selhub,J.; Jacques,P.F.; Rosenberg,I.H.; D'Agostino,R.B.; Wilson,P.W.; Wolf,P.A.
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 micromol 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