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A Mechanistic QSP Model of Alzheimer’s Disease Yields Insights into Pathophysiological and Therapeutic Mechanisms

Dr. Robert Sheehan
Senior Modeler, Rosa & Co. LLC
Dr. Colleen Witt
Principal Scientist, Rosa & Co. LLC

In this webinar we will discuss results from our paper with colleagues from Roche and Genentech that received the ISoP 2023 Outstanding Research Manuscript Award.

Alzheimer's disease (AD) is an inherently challenging disease to study, given the long time scales and the difficulties in measuring biochemical and physiological changes. QSP can help reduce uncertainty and guide clinical trial design. We developed a QSP model representing amyloid beta (Aβ) pathophysiology in AD. The model includes Aβ production and aggregation, transport of soluble species between brain, cerebrospinal fluid (CSF), and plasma, and pharmacokinetics, transport, and binding dynamics of multiple monoclonal antibodies, measuring response by PET and CSF/plasma biomarkers. Model components were calibrated to internal and literature data, including from clinical trials for anti‐Aβ monoclonal antibodies (mAbs).

In addition to predicting response to therapy, the model supports investigation of pathophysiological mechanisms and dynamics. For example, the model was initially developed for an apolipoprotein E (APOE) ɛ4 allele carrier as the first virtual patient (VP). We then implemented the known mechanistic effects of ApoE4 in the Platform and created an APOE ɛ4 noncarrier VP. We will demonstrate that with no other changes, the noncarrier VP’s predicted total Aβ burden and progression rate were consistent with literature data, suggesting that the known mechanistic ApoE4 effects are sufficient to explain the clinical differences.

In reproducing the impact of therapeutic mAb treatment on removal of aggregated Aβ, the model provided insight into the role of microglial activation. We will demonstrate why, to account for the observed Aβ clearance dynamics, the involvement and contribution to clearance by activated microglia must extend beyond the site of mAb binding.

The model can be used for exploration of other Aβ-directed therapies, or it can be expanded, e.g., to investigate additional AD mechanisms such as Tau pathology.