Optimal anti-amyloid-beta therapy for Alzheimer's disease via a personalized mathematical model.

Abstract

With the recent approval by the FDA of the first disease-modifying drug for Alzheimer's Disease (AD), personalized medicine will be increasingly important for appropriate management and counseling of patients with AD and those at risk. The growing availability of clinical biomarker data and data-driven computational modeling techniques provide an opportunity for new approaches to individualized AD therapeutic planning. In this paper, we develop a new mathematical model, based on AD cognitive, cerebrospinal fluid (CSF) and MRI biomarkers, to provide a personalized optimal treatment plan for individuals. This model is parameterized by biomarker data from the AD Neuroimaging Initiative (ADNI) cohort, a large multi-institutional database monitoring the natural history of subjects with AD and mild cognitive impairment (MCI). Optimal control theory is used to incorporate time-varying treatment controls and side-effects into the model, based on recent clinical trial data, to provide a personalized treatment regimen with anti-amyloid-beta therapy. In-silico treatment studies were conducted on the approved treatment, aducanumab, as well as on another promising anti-amyloid-beta therapy under evaluation, donanemab. Clinical trial simulations were conducted over both short-term (78 weeks) and long-term (10 years) periods with low-dose (6 mg/kg) and high-dose (10 mg/kg) regimens for aducanumab, and a single-dose regimen (1400 mg) for donanemab. Results confirm those of actual clinical trials showing a large and sustained effect of both aducanumab and donanemab on amyloid beta clearance. The effect on slowing cognitive decline was modest for both treatments, but greater for donanemab. This optimal treatment computational modeling framework can be applied to other single and combination treatments for both prediction and optimization, as well as incorporate new clinical trial data as it becomes available.