Disease-modifying effect of donepezil on APP/PS1 mice at different stages of Alzheimer's disease.

Despite Alzheimer's disease (AD) representing a significant global health concern, disease-modifying therapeutic options remain elusive. The use of animal models of the disease to develop drugs intended for the treatment of AD does not always predict their efficacy in clinical trials. Our research demonstrates the benefits of a drug-withdrawal approach to screening AD-modifying compounds, focussing on β-amyloid (Aβ)-related pathological changes in APP/PS1 transgenic mice at different stages of the disease. To assess the efficacy of this approach, we examined the AD-modifying effect of donepezil as a reference drug. A significant cognitive decline exhibited by APP/PS1 transgenic mice from 8.4 months of age was accompanied by progressive accumulation of Aβ plaques, decreased synaptophysin and vesicular acetylcholine transporter immunoexpression. Donepezil had a disease-modifying effect, slowing the deterioration of all the pathological markers studied when treatment was started in a pre-symptomatic stage of AD. However, in the group of mice with advanced stage of AD, such disease-modifying effects were not evident.