Effects of Low-Intensity Ultrasound on Amyloid-β Clearance in Early-Stage Alzheimer′s Disease: A Potential Role of Glymphatic Activity

Objective: Alzheimer′s disease (AD) involves impaired clearance of metabolic waste, including amyloid-β, potentially related to glymphatic dysfunction. Low-intensity ultrasound (LIUS) may facilitate solute clearance in the brain. This pilot study examined whether LIUS affects amyloid-β deposition and cognitive performance in early-stage AD, and whether MRI-derived changes in putative glymphatic activity could represent a possible underlying mechanism. Methods: This prospective pilot study (September 2022–February 2023) enrolled 10 amyloid-positive participants who underwent 4 weeks of LIUS treatment, including five apolipoprotein E4 (APOE4) carriers and five noncarriers. LIUS treatment involved sessions over 4 weeks. Magnetic resonance imaging (MRI) and amyloid PET scans were used to quantitatively analyze glymphatic activity, blood–brain barrier (BBB) integrity, microbleed occurrence, and amyloid deposition changes. Cognitive changes were assessed using neuropsychological tests. Results: All participants completed treatment without any significant adverse events. Neuropsychological testing demonstrated cognitive function improvements. Amyloid-β deposition decreased mainly in APOE4 carriers following LIUS. In addition, post-LIUS, the cerebral cortex showed increased putative glymphatic activity, although statistical significance was not maintained after multiple-comparison correction. No significant changes were observed in BBB integrity, microbleed occurrence, or brain volume. Conclusion: LIUS was safe and demonstrated both cognitive improvement and reduced amyloid deposition in early-stage AD. These effects may reflect several biological actions of LIUS, including the possibility of glymphatic enhancement. Further studies with larger cohorts and appropriate control groups are warranted to confirm these findings and draw more definitive conclusions. Trial Registration: Clinicaltrial.gov identifier: NCT05633095.