Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta

CPT Pharmacometrics Syst Pharmacol. 2017 Oct;6(10):676-685. doi: 10.1002/psp4.12249. Epub 2017 Sep 28.

Abstract

Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aβ) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas-cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human studies. Our model predicts that: (1) at least 1 year (2 years for preclinical AD) of treatment is needed to observe cognitive effects; (2) under the hypothesis with functional importance of Aβ, a 15% decrease in Aβ (using an imaging biomarker) is related to 15-20% cognition improvement by immunotherapy. Despite negative outcomes in clinical trials, Aβ continues to remain a prospective target demanding careful assessment of mechanistic effect and duration of trial design.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Drug Administration Schedule
  • Humans
  • Immunotherapy / methods*
  • Kinetics
  • Mice
  • Models, Statistical*
  • Molecular Targeted Therapy
  • Prospective Studies
  • Translational Medical Research

Substances

  • Amyloid beta-Peptides