FUS-Aducanumab
(2024)Objective
To evaluate safety and feasibility of combining focused ultrasound blood-brain barrier opening with aducanumab infusion to enhance amyloid removal in Alzheimer's disease
Study Summary
• Blood-brain barrier opening was transient (closed within 24-48 hours) with no serious neurological adverse events during 6-month treatment
• Proof-of-concept in 3 patients; excluded APOE ε4 carriers as risk mitigation
Intervention
Monthly aducanumab (1-6 mg/kg escalating dose) combined with MRI-guided focused ultrasound to open blood-brain barrier in targeted brain regions for 6 months
Inclusion Criteria
Age 50-85, mild cognitive impairment or mild Alzheimer disease dementia, amyloid SUVR >1.4 on florbetaben PET, elevated CSF P-tau (>21.7 pg/mL), APOE ε4 non-carriers only
Study Design
Arms: Single arm: Aducanumab + focused ultrasound (one hemisphere) vs untreated contralateral hemisphere as control
Patients per Arm: 3 participants total
Outcome
• Mean 32% SUVR reduction in treated regions after 6 monthly treatments
• No ARIA, no serious neurological adverse events; headaches most common AE
Bottom Line
In this proof-of-concept trial of 3 participants, combining focused ultrasound blood-brain barrier opening with aducanumab resulted in numerically greater amyloid reduction in treated regions (48-63 percentage points greater) compared to untreated contralateral regions, with acceptable safety profile in APOE ε4 non-carriers
Major Points
- Proof-of-concept, single-arm trial in 3 participants with mild Alzheimer's disease
- MRI-guided focused ultrasound temporarily opened blood-brain barrier (closed within 24-48 hours)
- Six monthly combination treatments with escalating aducanumab doses (1-6 mg/kg)
- Amyloid reduction 48-63 percentage points greater in FUS-treated regions vs contralateral untreated regions
- Mean 32% SUVR reduction in treated regions combined across 3 participants
- APOE ε4 carriers excluded as risk mitigation strategy
- No ARIA observed; aducanumab dose capped at 6 mg/kg (below standard 10 mg/kg)
- Headaches were most common adverse event; no serious neurological events during treatment phase
- One participant showed cognitive decline at 30-day follow-up on RBANS (76→61)
Study Design
- Study Type
- Investigator-initiated, prospective, open-label, single-group, single-institution, proof-of-concept trial
- Randomization
- No
- Blinding
- Open-label; contralateral hemisphere served as internal control
- Sample Size
- 3
- Follow-up
- 6 months treatment + 180 days follow-up (Participant 1), 90 days (Participant 2), 30 days (Participant 3)
- Centers
- 1
- Countries
- United States
Primary Outcome
Definition: Change in amyloid-beta levels (centiloids) from baseline to 26 weeks in FUS-treated regions vs contralateral untreated regions
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - |
Limitations & Criticisms
- Very small sample size (n=3) limits generalizability
- Open-label design without true randomization
- APOE ε4 carriers excluded - cannot assess safety in highest-risk population for ARIA
- Aducanumab dose capped at 6 mg/kg (below standard 10 mg/kg) as risk mitigation
- Staggered follow-up (30-180 days) limits consistent outcome assessment
- Did not directly measure antibody penetration - enhanced delivery inferred from amyloid reduction
- One participant showed cognitive decline during follow-up
- Single institution experience
- Contralateral hemisphere as control may not account for systemic effects of treatment
Citation
N Engl J Med 2024;390:55-62