Although the first generation of immunotherapies for Alzheimer's disease (AD) are now clinically approved, further optimization could improve both efficacy and safety. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (Aβ) antibodies. We show that introduction of asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to Aβ while mitigating TfR-related hematology liabilities. ATVcisLALA:Aβ maintained the ability to induce microglial phagocytosis of Aβ bothex vivoandin vivo. Mice treated with ATVcisLALA:Aβ exhibited broad brain parenchymal antibody distribution and enhanced plaque target engagement, whereas anti-Aβ IgG was highly localized to arterial perivascular spaces where cerebral amyloid angiopathy (CAA) is commonly found and likely plays a role in induction of amyloid-related imaging abnormalities (ARIA). Importantly, ATVcisLALA:Aβ mitigated ARIA-like lesions and vascular inflammation associated with anti-Aβ treatment in a mouse model of amyloid deposition. Taken together, ATVcisLALAhas the potential to significantly improve both safety and efficacy of Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.