Quantitative systems pharmacology model of Alzheimer’s disease to study efficacy of combinatorial therapy on multiple pathology components

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AbstractBackgroundImmunotherapies targeting tau or Aβ remain the key focus for neurologists. But low brain penetration and limited scope of targeting may restrict efficacy. This restriction may be overcome by combinations with other treatments targeting protein degradation systems. Quantitative systems pharmacology model allows for integration of available information from multiple preclinical studies to simulate clinical studies. The goal was to develop the translational model of key AD markers, verified and validated on the literature data and to simulate effects of combinations.MethodPredeveloped Ab and tau pathology submodels have been merged through the model of intracellular protein degradation systems (proteasome, autophagy), which is known to fail progressively in AD. Literature data (concentration baselines and dynamics, SUVR) from mice and human have been used for calibration. Multiple in vitro data for intracellular dynamics perturbations (rapamycin, proteasome inhibitors, vinblastine) available from the literature were used to estimate the intracellular regulation parameters. Immunotherapy mechanism is described through 1) binding of antibodies and prevention of seeding and growth of aggregates, 2) activation of microglia for Ab degradation. Data from clinical studies for immunotherapy (BAN2401) and BACE inhibitor (verubecestat) have been used for retrospective model validation, together with data for treatment by rapamycin, calpain inhibitors, proteasome activation in mouse AD models.ResultModel correctly describes the Aβ and tau accumulation and mutual exacerbation in mice and humans. It correctly predicts effect of rapamycin, calpain inhibitors, proteasome activation on tau tangles in tau‐transgenic mouse and absence of effect of Aβ targeting on tau pathology markers in humans. Simulation of Aβ immunotherapy starting from 65 years (Braak stage 3‐4), predicts 80% Aβ plaque difference vs placebo within 2 years, without effect on tau markers. Rapamycin is predicted to clear tau pathology, with modest efficacy (up to 30‐40%) of Aβ clearing. An example of combination, anti‐Aβ immunotherapy with rapamycin is most effective in retarding both pathologies (up to 80‐90%) in hippocampus.ConclusionQSP modeling allows for choice of combinations of newly emerging biologics combined with targeting cell metabolism, to lead optimization and increase of treatment efficacy.