Background . Memantine is an approved symptomatic treatment for moderate to severe Alzheimer's Disease(AD) active on the excitotoxic effects of hyperactive glutamatergic transmission. The mechanism of the effect of memantine in AD patients is poorly known. The default mode network (DMN) is hypoactive in AD and is under glutamatergic control. Objective . To assess the effect of memantine on the activity of the DMN in moderate to severe AD. Methods. fMRI data of 15 moderate to severe AD patients, 7 (age 77±7, MMSE 16±4) treated with memantine and 8 with placebo (age 75±6, MMSE 13±4), were acquired at baseline (T0) and after 6 months of treatment (T6). Resting state components were extracted after spatial normalization on individual patients with independent component analysis. The consistency of the components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre- defined template. Voxel-based statistical analyses were performed to study the change of DMN activity from T0 to T6 in the two groups. Results . At T0, the two groups showed similar DMN activity except in the precuneus, where the treated showed slightly greater activity (p