Abstract Rationale The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD). Focused ultrasound applied together with microbubbles (FUS +MB ) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS +MB is safe, however the effects of FUS +MB on human BBB cells, especially in the context of AD, remain sparsely investigated. Methods Here we generated BBB cells (induced brain endothelial cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 ( APOE4 , high AD risk) and allele E3 ( APOE3 , lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We then developed a human sporadic AD BBB cell platform to investigate the effects of FUS +MB on BBB cells and screen for the delivery of two potentially therapeutic AD antibodies. Results We utilized this robust and reproducible human BBB model to demonstrate increased delivery of therapeutic AD antibodies across the BBB following FUS +MB treatment, including an analogue of Aducanumab (Aduhelm TM ; anti-amyloid-β) and a novel anti-Tau antibody RNF5. Our results also demonstrate the safety of FUS +MB indicated by minimal changes in the cell transcriptome as well as little or no changes in cell viability and inflammatory responses within the first 24 h post FUS +MB . Finally, we report a more physiologically relevant hydrogel-based 2.5D BBB model as a key development for FUS +MB -mediated drug delivery screening, with potentially higher translational utility. Conclusion Our results demonstrate an important translatable patient BBB cell model for identifying FUS +MB -deliverable drugs and screening for cell- and patient-specific effects of FUS +MB , accelerating the use of FUS +MB as a therapeutic modality in AD. One Sentence Summary Focused ultrasound increases the in vitro delivery of therapeutic antibodies Aducanumab and anti-Tau in a sporadic Alzheimer’s disease patient-derived blood-brain barrier cell model.

A sporadic Alzheimer’s blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies