What is the role of monoclonal antibodies (mAbs) in the treatment of Alzheimer's disease?

Monoclonal Antibodies for Alzheimer's Disease: Current Role and Considerations

Monoclonal antibodies targeting amyloid-β represent a significant breakthrough in Alzheimer's disease treatment, with lecanemab (Leqembi) and donanemab (Kisunla) demonstrating the ability to slow clinical decline in early-stage Alzheimer's disease, though they come with important safety considerations including ARIA (amyloid-related imaging abnormalities) that require careful monitoring. 1, 2

FDA-Approved Monoclonal Antibodies

Currently, there are two primary anti-amyloid monoclonal antibodies available for Alzheimer's disease:

1. Lecanemab (Leqembi):

   • Received traditional (full) FDA approval in July 2023
   • Indicated for early-stage Alzheimer's disease (MCI or mild dementia)
   • CMS agreed to reimburse when patients are registered in a CMS-approved registry 1

2. Donanemab (Kisunla):

   • FDA advisory panel unanimously recommended traditional approval in June 2024 1
   • Also targets early-stage Alzheimer's disease

3. Aducanumab (Aduhelm):

   • Received accelerated approval in June 2021
   • Development and sales have been discontinued due to limited use after CMS did not support payment 1

Mechanism and Efficacy

These monoclonal antibodies work by targeting and clearing amyloid-β plaques in the brain:

• They are the first disease-modifying therapies that intervene in the basic biological processes of Alzheimer's disease 2
• Meta-analyses show significant reduction in amyloid burden (SMD -0.88) 3
• Clinical efficacy measured by CDR-SB (Clinical Dementia Rating-Sum of Boxes) shows statistically significant but modest slowing of decline (MD -0.15) 3
• Recent clinical trials of lecanemab and donanemab have put monoclonal antibodies "back at center stage" for Alzheimer's treatment 1

Safety Considerations

The primary safety concern with these treatments is ARIA (amyloid-related imaging abnormalities):

• Meta-analyses show risk ratios of 10.65 for ARIA-E (edema) and 1.75 for ARIA-H (hemorrhage) 3
• Patients require close monitoring during treatment initiation 2
• APOE genotype influences ARIA risk, making genetic testing important for treatment planning 1
• Brain MRI scans are required for monitoring ARIA 1

Patient Selection

Appropriate patient selection is critical:

• Indicated for patients with MCI or mild dementia due to Alzheimer's disease ("early-stage AD") 1
• Requires confirmation of amyloid pathology through:
  • Amyloid PET imaging (now reimbursable for Medicare beneficiaries as of October 2023) 1
  • CSF biomarkers (several new assays have received FDA clearance) 1
  • Emerging blood-based biomarkers may serve as pre-screeners to reduce the need for more invasive testing 1

Implementation Challenges

Several challenges exist in implementing these treatments:

1. Healthcare System Readiness:

   • Demand for timely detection and accurate diagnosis could overwhelm unprepared healthcare systems 1
   • Treatment requires high proficiency and sufficient resources including multidisciplinary teams 1

2. Specialist Availability:

   • Too few specialists are currently available to meet potential demand 1
   • New models of hub-and-spoke specialist-primary care collaborations may be needed 1

3. Monitoring Requirements:

   • Regular MRI monitoring for ARIA
   • Infusion reactions require monitoring during administration 2

Future Directions

The field continues to evolve:

• Success of current monoclonal antibodies will likely foster development of:
  • More anti-amyloid monoclonal antibodies
  • Other types of anti-amyloid therapies
  • Treatments targeting other aspects of Alzheimer's biology 2
• Desirable features for next-generation therapies include:
  • Less frequent ARIA
  • More convenient administration
  • Greater efficacy 2
• Blood-based biomarkers are being developed to improve screening efficiency and reduce costs 1

Practical Considerations

When considering monoclonal antibody treatment:

• Confirm diagnosis with appropriate biomarkers (amyloid PET or CSF testing)
• Perform baseline MRI to rule out contraindications
• Consider APOE genotyping to assess ARIA risk
• Ensure adequate monitoring capabilities for ARIA and infusion reactions
• Discuss modest clinical benefits versus potential risks with patients and caregivers
• Consider cost implications and insurance coverage

While these treatments represent a significant advancement in Alzheimer's disease therapy, the risk-benefit profile continues to be evaluated, with ongoing research needed to clarify the long-term impact of ARIA events and factors predicting their onset 3.