Fluoroethylnormemantine (FENM, RST-01) shows different pharmacological properties from Memantine. The drug is neuroprotective in pharmacological and transgenic mouse models of Alzheimer's disease (AD), particularly limiting the neuroinflammatory response to amyloid-β (Aβ) accumulation. In order to define early therapeutic intervention aimed at preventing AD and targeting the early activation of proinflammatory pathways, we examined the impact of chronic FENM treatment starting presymptomatically in APP/PSEN1 (APP/PS1) mice. APP/PS1 (32 males and 36 females) and wild-type (WT, 23 males and 36 females) mice received FENM (0, 1, and 5 mg/kg/day) in the drinking bottle between 3 and 12 months of age. They were tested once a month for spontaneous alternation and, at the end of the treatment, for object recognition, water-maze learning, and passive avoidance. Amyloid plaques, astrocytes, and microglia were assessed by immunofluorescence, and guanidine-soluble and insoluble Aβ levels were determined in the hippocampal formation. Spontaneous alternation performances regularly decreased in APP/PS1, but not in WT mice. The FENM treatments (1 and 5 mg/kg) prevented the deficit. At 12 months of age, APP/PS1 treated with 1 mg/kg FENM showed significant improvements in all behavioral procedures tested. The astroglial reaction was not significantly attenuated by FENM in the , and polymorph layer of the dentate gyrus. The microglial reaction was significantly decreased in the two latter areas. In the polymorph layer, a significant effect on amyloid plaques was measured. Global analyses of amyloid load showed attenuations of soluble and insoluble Aβ levels and a significant decrease in the level of insoluble Aβ. Moreover, significant negative correlations were observed for FENM impacts on amyloid load or microglial activation and the alternation score. FENM confirmed, under a chronic presymptomatic treatment, its neuroprotective efficacy in AD. Our data particularly suggested that an impact on Aβ and microglia could be related to the preservation of cognitive functions.