Degeneration of cortical glutamatergic projections may contribute to the cognitive decline in Alzheimer disease (AD). To evaluate whether 1glutamate system stimulation might confer symptomatic benefit, we administered D-cycloserine, a putative partial indirect agonist at certain N-methyl-D-aspartate (NMDA) glutamate receptors, to 12 patients with probable AD. The patients (seven men, five women) had a mean age of 65 +/- 8.4 years; Mini Mental State Examination scores ranged from 15 to 25. A dose escalation phase, in which cycloserine was given in daily oral doses from 25 to 500 mg (total of six dose levels, 1 week per dose), was followed by a "best dose" crossover comparison with placebo under double-blind conditions. The crossover phase consisted of 2 weeks of cycloserine and 2 weeks of placebo, separated by a 1-week washout period. We observed no significant or consistent effect on neuropsychological outcome measures. The results suggest that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of Alzheimer dementia.