Quantitative Systems Pharmacology Analysis of Hippocampal Volume Trajectory by APOE Genotype and Neuroprotective Effects of Valiltramiprosate/ALZ‐801 in Early AD

QSP analysis supports the hypothesis that acceleration of Aβ aggregation is the initial step in Early AD triggering an increase in toxic oligomers that drives AD neurodegeneration, measured by hippocampal atrophy, followed by subsequent rapid cognitive decline. Valiltramiprosate intervention in Early AD produces an exposure, age and stage of disease-dependent reduction in hippocampal atrophy in all APOE genotypes, with the magnitude of benefit greatest at early symptomatic disease stage. The neuroprotective effect is driven by an exposure-related reduction of Aβ oligomers and protofibrils that blunts the pathological amyloid cascade in AD.