The Establishment And Application Of Alzheimer’s Disease Progression Model

Alzheimer’s disease(AD)is a degenerative neurological disease in geriatric population,which is characterized by gradual memory loss and cognitive deterioration.Theoretically,the longitudinal disease status of AD subjects in clinical trials composed of natural disease progression,placebo effect and the treatment effect.Therefore,in order to determine the clinical efficacy of the novel anti-AD traditional Chinese medicine and facilitate trial design effectively,this research was conducted to qualify and analysis the AD disease progression by using modelling and simulation technique.First,placebo-controlled randomized AD clinical trials were systemically searched in public databases by using ADAS-cog scale(the cognitive subscale of the Alzheimer’s Disease Assessment Scale)to evaluate the cognitive function of AD patients.Longitudinal placebo response and the corresponding demographic/trial information were extracted to establish a disease progression model.Covariate screening and subgroup analyses were performed to identify potential factors affecting the disease progression rate.Monte-Carlo method was used to simulated the placebo responses under different scenarios.The final model indicated the typical AD disease progression rate was 5.82 points per year.Baseline ADAS-cog score and age were two important factors influencing the disease progression rate.Besides,disease progression rate was not found to be affected by add-on trial design,but showed some variations among different geographic regions.Second,the neuropsychiatric symptoms(NPS)in AD patients were also quantitatively described by modelling the time-course of the change in NPI scale(neuropsychiatric inventory).Potential affecting factors were tested as covariates.The analyzed results indicated that the theoretical maximal placebo responses of NPS were reached at week 4,after which the NPS continued to decline.The baseline NPI score had a significant impact on the placebo responses,where AD subjects with higher baseline NPI score tended to show greater placebo responses.Model simulation suggested that the deterioration trend of cognitive impairment and NPS is not consistent.Based on the two disease progression models,a population pharmacodynamic model of the current standard therapies(cholinesterase inhibitors and memantine)was built to quantitatively analyze the dose-time-efficacy relationship.The final model found that the current AD drugs showed positive treatment efficacy in delaying cognitive decline,but none of them could improve the NPS effectively in AD patients.Besides,the model enabled indirect comparison of efficacy between different drugs under the circumstance of lacking head-to-head clinical trial.The model simulations could also serve as historical positive control in further AD trials.Finally,the efficacy of tradition Chinese medicine in clinical trials were compared and evaluated according to the above established models.The analyzed results determined the therapeutic effect of huperzine A,yishenhuazhuo decoction and Ninjin’yoeito to delay cognitive decline.High dose of Mengshi Guntan pills combined with olanzapine,and Yokukansan could improve NPS in AD patients effectively.These traditional herbal medicines had high potential to be exploited,and the established AD models in this research provided key evidences to support the further clinical development.