BACKGROUND: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced 
amyloid pathology in Alzheimer's disease (AD) trials; however, it is 
controversial whether it also improved cognition, which has been suggested would 
require a sufficiently high cumulative dose of the antibody in the brain. 
Therapeutic ultrasound, in contrast, has only begun to be investigated in human 
AD clinical trials. We have previously shown that scanning ultrasound in 
combination with intravenously injected microbubbles (SUS), which temporarily 
and safely opens the blood-brain barrier (BBB), removes amyloid and restores 
cognition in APP23 mice. However, there has been no direct testing of how the 
effects of SUS compare to immunotherapy or whether a combination therapy is more 
effective.
METHODS: In a study comprising four treatment arms, we tested the efficacy of an 
Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, 
in APP23 mice (aged 13-22 months), using sham as a control. The active place 
avoidance (APA) test was used to test spatial memory, and histology and ELISA 
were used to measure amyloid. Brain antibody levels were also determined.
RESULTS: We found that both Adu and SUS reduced the total plaque area in the 
hippocampus with no additive effect observed with the combination treatment 
(SUS + Adu). Whereas in the cortex where there was a trend towards reducing the 
total plaque area from either Adu or SUS, only the combination treatment yielded 
a statistically significant decrease in total plaque area compared to sham. Only 
the SUS and SUS + Adu groups included animals that had their plaque load reduced 
to below 1% from above 10%. There was a robust improvement in spatial memory for 
the SUS + Adu group only, and in this group the level of Adu, when measured 
3 days post-treatment, was 5-fold higher compared to those mice that received 
Adu on its own. Together, these findings suggest that SUS should be considered 
as a treatment option for AD. Alternatively, a combination trial using 
Aducanumab together with ultrasound to increase brain levels of the antibody may 
be warranted.