A Quantitative Systems Pharmacology Model That Describes Neurofilament Light Dynamics During Alzheimer's Disease Progression.

Abstract

Neurofilament proteins are important constituents of neuronal cytoskeleton, along with microtubules. An increased concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and plasma is considered a potential biomarker of axonal degeneration, which occurs in various neurodegenerative diseases including Alzheimer's disease (AD). The goal of this study was to develop a QSP model describing the change in the concentration of NfL in the brain, CSF, and plasma during the progression of AD for populations of AD patients manifesting different combinations of biomarkers (amyloid, tau, brain atrophy), to estimate the contributions of different mechanisms to neurodegeneration. The model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which depend on cytoskeletal degradation and the release of neurofilament proteins from degenerated axons into cerebrospinal fluid and plasma. These processes are driven by disruptions of neuron homeostasis in AD, such as changes in protein degradation, axonal transport deficits, and the accumulation of pathological amyloid and hyperphosphorylated tau. The model was validated against clinical data and demonstrated correct predictions for anti-tau therapy while showing a tendency to overestimate efficacy of anti-amyloid therapy (lecanemab). This supports the idea that amyloid therapy contribution to neurodegeneration is limited, and that treatment should focus on other mechanisms.