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

Overview

Journal CPT Pharmacometrics Syst Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2017 Sep 16

PMID 28913897

Citations 10

Authors

Tatiana Karelina

Oleg Demin Jr

Oleg Demin

Sridhar Duvvuri

Timothy Nicholas

Affiliations

Soon will be listed here.

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.

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