P4‐334: Combination of memantine and donepezil reverses cognitive deficits in transgenic mice with both amyloid‐beta plaques and neurofibrillary tangles

Moderate to severe Alzheimer's disease (AD) is characterized by a high degree of cognitive, functional, and behavioral dysfunction. There are relatively few treatments available for this stage of illness, and these appear to provide symptomatic benefit without altering the course of the disease. The most widespread symptomatic treatments for AD are acetylcholinesterase inhibitors, including donepezil, which provide temporary cognitive benefits. In addition to acetylcholinesterase inhibitors, several clinical studies have shown support for the use of the NMDA receptor antagonist memantine, either as monotherapy or in combination with a cholinesterase inhibitor for moderate to severe AD. In this study, a battery of cognitive tasks was used to test the effects of donepezil, memantine, and combined treatment in 3xTg-AD mice (PS1M146V, APPSwe and tauP301L). These transgenic mice develop both plaques and tangles in a region-specific and age-progressive manner, and also exhibit progressive learning deficits. Donepezil (1mg/kg/day), memantine (30mg/kg/day), donepezil-memantine combination, or vehicle (saline) were administered orally via drinking water to cohorts of adult (15 months of age; severe pathology) and young mice (6 months of age; mild pathology), for three months. In both adult and young mice, memantine and donepezil-memantine combination treatment significantly improved spatial memory (both acquisition and retention), compared to the vehicle-treated animals, whereas donepezil improved the retention, but not acquisition, of spatial memory. These results suggest that memantine treatment, or combination therapy using donepezil and memantine, is more effective than donepezil monotherapy at improving cognitive performance in both young and old mice demonstrating cognitive deficits and AD-like pathology.