Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies

The blood-brain barrier (BBB) limits brain uptake of therapeutic antibodies. It is believed that the BBB is disrupted in Alzheimer’s disease (AD), potentially increasing drug permeability de facto. Here we compared active versus passive brain uptake of systemically dosed antibodies (anti-transferrin receptor [TfR] bispecific versus control antibody) in mouse models of AD. We first confirmed BBB disruption in a mouse model of multiple sclerosis as a positive control. Importantly, we found that BBB permeability was vastly spared in mouse models of AD, including PS2-APP, Tau transgenics, and APOE4 knockin mice. Brain levels of TfR in mouse models or in human cases of AD resembled controls, suggesting target engagement of TfR bispecific is not limited. Furthermore, infarcts from human AD brain showed similar occurrences compared to age-matched controls. These results question the widely held view that the BBB is largely disrupted in AD, raising concern about assumptions of drug permeability in disease. •EAE-induced mice display BBB permeability to therapeutically dosed antibodies•Intact BBB in multiple mouse models of AD restricts passive antibody uptake in brain•Brain infarcts and TfR levels are similar in human AD and control samples•BBB-crossing strategies are necessary to enhance delivery of antibody therapeutics It is generally believed that neurodegeneration is accompanied by BBB dysfunction, potentially increasing drug bioavailability in the CNS. Bien-Ly et al. report that AD mouse models lack widespread BBB disruption and display restricted passive permeability to therapeutic antibodies.