Serum homocysteine is increased, and correlates inversely with cognitive scores, in Alzheimer's disease (AD), vascular dementia and "age-associated memory impairment". Elevated levels might signal accelerated cognitive decline, although this remains to be established. We therefore repeated Mini-Mental State Examinations, together with additional ADAS-Cog assessments, in 32 healthy elderly individuals to determine whether prior homocysteine levels predicted cognitive changes over a 5-year period. Homocysteine predicted follow-up cognitive scores and rate of decline in cognitive performance independently of age, sex, education, renal function, vitamin B status, smoking and hypertension (p < 0.001). Homocysteine predicted word recall (p = 0.01), orientation (p = 0.02) and constructional praxis scores (p < 0.0001). One subject, with the second highest initial homocysteine, had developed probable AD at follow-up. Fasting total serum homocysteine appears to be an independent predictor of cognitive decline in healthy elderly and exerts a maximal effect on spatial copying skills. Copyright 2001 S. Karger AG, Basel