Targeting Soluble Amyloid Oligomers in Alzheimer's Disease: A Hypothetical Model Study Comparing Intrathecal Pseudodelivery of mAbs Against Intravenous Administration.

Background/objective: Neurotoxic soluble amyloid-β (Aβ) oligomers are key drivers of Alzheimer's pathology, with evidence suggesting that early targeting of these soluble forms may slow disease progression. Traditional intravenous (IV) monoclonal antibodies (mAbs) face challenges, including limited brain penetration and risks such as amyloid-related imaging abnormalities (ARIA). This hypothetical study aimed to model amyloid dynamics in early-to-moderate Alzheimer's disease (AD) and compare the efficacy of IV mAn with intrathecal pseudodelivery, a novel method that confines mAbs in a subcutaneous reservoir for selective amyloid clearance in cerebrospinal fluid (CSF) without systemic exposure.

Methods: A mathematical framework was employed to simulate Aβ dynamics in patients with early-to-moderate AD. Two therapeutic approaches were compared: IV mAb and intrathecal pseudodelivery of mAb. The model incorporated amyloid kinetics, mAb affinity, protofibril size, and therapy-induced clearance rates to evaluate the impact of both methods on amyloid reduction, PET negativity timelines, and the risk of ARIA.

Results: Intrathecal pseudodelivery significantly accelerated Aβ clearance compared to IV administration, achieving amyloid PET scan negativity by month 132, as opposed to month 150 with IV mAb. This method demonstrated no ARIA risk and reduced amyloid reaccumulation. By targeting soluble Aβ species more effectively, intrathecal pseudodelivery emerged as a safer and more efficient strategy for early AD intervention.

Conclusions: Intrathecal pseudodelivery offers a promising alternative to IV mAbs, overcoming challenges associated with blood-brain barrier penetration and systemic side effects. Further research should focus on optimizing this approach and exploring combination therapies to enhance clinical outcomes in AD.