Progressive amyloid deposition and cognitive decline characterize AD. In preclinical studies, the BBB with FUS reduced plaque. In this Phase-1 trial, we tested the safety of repeated BBB opening with FUS in AD patients.

Probable AD patients with mild to moderate dementia symptoms were screened. A high amyloid burden was defined by a standardized uptake value 25% greater than the cerebellum using amyloid positron emission tomography (PET). BBB was opened in five different locations with a high amyloid burden at three time-points two weeks apart.  The primary outcome variable was the absence of cognitive decline, hemorrhage, new onset of seizures, or neurological deficits. We also assessed BBB opening (with dynamic contrast imaging) and postoperative PET amyloid levels.

Ten patients were screened, six were enrolled, and five were treated. The targeted brain regions included the hippocampus, entorhinal cortex, thalamus, frontal cortex, parietal cortex. No hemorrhage and cerebral edema were observed. BBB opening was focal, immediate, and no contrast enhancement was observed one day postoperative. No serious adverse events were recorded. A total of seven adverse events were reported, most commonly confusion. Two patients reported worsening in cognition at day-1 and five weeks after treatment, respectively. The amyloid reduction varied between 1-15% from baseline without significant differences between different tissue types (gray versus white matter).

BBB opening with FUS is safe and feasible in AD patients. There is the initial evidence of amyloid reduction. This strategy needs further testing in a larger cohort as a potential therapeutic for AD.