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Alzheimer disease ( AD ) is a devastating neurodegenerative disorder with high unmet medical need. Drug development is hampered by limited understanding of the disease and its driving factors. Quantitative Systems Pharmacology ( QSP ) modeling provides a comprehensive quantitative framework to evaluate the relevance of biological mechanisms in the context of disease and to predict the efficacy of novel treatments. Here, we report a  QSP  model for  AD  with a particular focus on investigating the relevance of dysregulation of cholesterol and sphingolipids. We show that our model captures the modulation of several biomarkers in subjects with  AD , as well as the response to pharmacological interventions. We evaluate the impact of targeting the sphingosine‐1‐phosphate 5 receptor (S1 PR 5) as a potential novel treatment option for  AD , and model predictions increase our confidence in this novel disease pathway. Future applications for the  QSP  model are in validation of further targets and identification of potential treatment response biomarkers.

Quantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option