Ultrasound-induced blood–brain barrier opening in Alzheimer’s disease: a systematic review of clinical studies

Abstract

BACKGROUND: Focused ultrasound (FUS) has emerged as a non-invasive approach to transiently open the blood-brain barrier (BBB) and facilitate therapeutic delivery in Alzheimer's disease (AD). This systematic review evaluates current clinical evidence regarding the feasibility, safety, and reported biological and clinical outcomes of FUS-mediated BBB opening. METHOD: A systematic search of PubMed, Scopus, and Web of Science was conducted in accordance with PRISMA 2020 guidelines and supplemented by Google Scholar. Human clinical studies employing FUS-induced BBB opening in AD were included. Risk of bias was assessed using the ROBINS-I tool for non-randomized studies. RESULTS: From an initial screening of 587 records, 27 studies met the inclusion criteria. Across these studies, FUS-mediated BBB opening was generally feasible and well tolerated, with no reports of irreversible procedure-related adverse events. Reported adverse effects were typically mild and transient, including localized headache, fatigue, or imaging-detected edema. Exploratory findings included heterogeneous changes in cognitive measures and regional amyloid-β biomarkers assessed by neuroimaging or cerebrospinal fluid analysis. Substantial variability in study design, target regions, sonication parameters, and outcome measures limited quantitative synthesis and definitive interpretation. CONCLUSION: Current clinical evidence supports the short-term feasibility and safety of FUS-mediated BBB opening in AD. However, the available data remain preliminary, and well-designed randomized controlled trials with larger cohorts, standardized imaging and cognitive endpoints, and longer follow-up are required to determine therapeutic efficacy and sustained clinical benefit.