Cognitive evaluation of disease-modifying efficacy of galantamine and memantine in the APP23 model

The  four compounds currently used for treatment of AD (donepezil, rivastigmine, galantamine and memantine) provide symptomatic relief.   Both galantamine and memantine have been assigned neuroprotective, disease- modifying capabilities. However to date, the disease modifying efficacy of these agents has been a matter of debate.The goal of this study was to evaluate the disease-modifying efficacy of chronic treatment of both (separately , not combined) compounds, in the APP23 mouse model of AD. The APP23 model displays an age-related decline in visual—spatial learning capacities. It is thought that cholinergic dysfunction, as indicated by decreased acetylcholinesterase and choline acetyltransferase activity levels in basal forebrain nuclei, and additional alterations in other neurotransmission system drives the cognitive decline observed in APP23 mice.

 Analogous to clinical trial design, the authors employed a withdrawal design to investigate putative disease-modifying capacities of galantamine and memantine. Outcome parameters used to assess the putative disease-modifying efficacy of both compounds were MWM acquisition and probe trial performance. 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. Data showed that  low dose galantamine significantly improved spatial accuracy during probe trial. Memantine improved acquisition performance (path length) and spatial accuracy during probe trial in a dosedependent manner. These data are interpreted as demonstrating disease modifying efficacy on the cognitive impairment in the APP23 model. However, the authors go on to state that the data set did not allow statements regarding true neuroprotective effects in APP23 brain. An assessment of the neuroprotective activity of these compounds would require additional studies including, stereological evaluation of hippocampal volume, cell densities and/or cell counts.