Learning from amyloid trials in Alzheimer's disease. A virtual patient analysis using a quantitative systems pharmacology approach.

ABSTRACT:

Background

Many trials of amyloid-modulating agents fail to improve cognitive outcome in Alzheimer's disease despite substantial reduction of amyloid β levels.

Methods

We applied a mechanism-based Quantitative Systems Pharmacology model exploring the pharmacodynamic interactions of apolipoprotein E (APOE), Catechol -O -methyl Transferase (COMTVal158Met), and 5-HT transporter (5-HTTLPR) rs25531 genotypes and aducanumab.

Results

The model predicts large clinical variability. Anticipated placebo differences on Alzheimer's Disease Assessment Scale (ADAS)-COG in the aducanumab ENGAGE and EMERGE ranged from 0.77 worsening to 1.56 points improvement, depending on the genotype-comedication combination. 5-HTTLPR L/L subjects are found to be the most resilient. Virtual patient

SUBMITTER: Geerts H 

PROVIDER: S-EPMC7983876 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature