Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model describing Alzheimer's disease pathophysiology and...

Lecanemab, an anti-amyloid antibody, has demonstrated a significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD). A mechanistic Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model was developed to capture the temporal and biological complexity of AD progression. This QSP model incorporates three interlinked modules reflecting core aspects of AD pathology: Aβ accumulation, tau pathology, and cognitive decline, where Aβ accumulation promotes tau pathology, which leads to neuronal damage and cognitive impairment. A large multivariate dataset was assembled from 4056 subjects participating in lecanemab studies and the Alzheimer's Disease Neuroimaging Initiative (ADNI) to inform and validate the model. Virtual populations-based model simulations successfully reproduced the hallmark cascade of AD pathology, consistent with the well-known Jack curve, from amyloid buildup to tau spread and cognitive decline over decades. Simulations accurately predicted all endpoints evaluated from the lecanemab trials and were further validated against data from other anti-Aβ therapies. Importantly, the model revealed that Aβ protofibrils are more potent drivers of tau pathology than plaques. In summary, the Neuro-Dynamic QSP model is the first of its kind to mechanistically link amyloid accumulation, tau pathology, and cognitive decline in AD, providing a powerful framework for simulating clinical scenarios and understanding disease mechanisms.