Development of a quantitative semi-mechanistic model of Alzheimer's disease based on the amyloid/tau/neurodegeneration framework (the Q-ATN model)

Abstract

Introduction: A quantitative model of Alzheimer's disease (AD) based on the amyloid/tau/neurodegeneration biomarker framework (Q-ATN model) was developed to sequentially link amyloid positron emission tomography (PET), tau PET, medial temporal cortical thickness, and clinical outcome (Clinical Dementia Rating - Sum of Boxes; CDR-SB).

Methods: Published data and biologically plausible mechanisms were used to construct, calibrate, and validate the model. Clinical trial simulations were performed for different anti-amyloid antibodies, including a 5-year simulation of subcutaneous gantenerumab treatment.

Results: The simulated time-course of biomarkers and CDR-SB was consistent with natural history studies and described the effects of several anti-amyloid antibodies observed in trials with positive and negative (or non-significant) outcomes. The 5-year simulation predicts that the beneficial effects of continued anti-amyloid treatment should increase markedly over time.

Discussion: The Q-ATN model offers a novel approach for linking amyloid PET to CDR-SB, and provides theoretical support for the potential clinical benefit of anti-amyloid therapy.

Highlights: A semi-mechanistic model was developed to link amyloid/tau/neurodegeneration biomarkers to clinical outcome (Q-ATN model). The Q-ATN model describes the disease progression seen in natural history studies. Model simulations agree well with mean data from the aducanumab EMERGE study. A 5-year simulation of gantenerumab predicts greater benefit with longer treatment.

Keywords: Clinical Dementia Rating - Sum of Boxes; aducanumab; amyloid; anti-amyloid therapies; bapineuzumab; biomarkers; donanemab; gantenerumab; lecanemab; mathematical model; neurodegeneration; tau.