With increasing knowledge of molecular, biochemical and cellular events causing synaptic dysfunction and neurodegeneration in Alzheimer-diseased brain, preventive treatment strategies are emerging. Neuroprotective capacities have been attributed to galantamine and memantine. The age-dependent cognitive decline in the APP23 model was employed to evaluate disease-modifying efficacy of chronic treatment with both compounds. At age 6 weeks, heterozygous APP23 mice were subcutaneously implanted with osmotic pumps delivering saline, galantamine (1.3 or 2.6 mg/kg/day) or memantine (7.2 or 14.4 mg/kg/day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects. Subsequently, cognitive evaluation in the Morris water maze commenced. Galantamine low dose significantly improved spatial accuracy during probe trial. Memantine improved acquisition performance (path length) and spatial accuracy during probe trial in a dose-dependent manner. This is the first study reporting disease-modifying efficacy of galantamine and memantine in transgenic mice modeling Alzheimer's disease.