What is the role of infusions, such as intravenous immunoglobulin (IVIG) or aducanumab, in the treatment of Alzheimer's disease?

Infusion Therapies for Alzheimer's Disease: Current Evidence and Recommendations

Monoclonal antibody therapies targeting amyloid plaques, such as lecanemab, donanemab, and aducanumab, are the only FDA-approved disease-modifying infusion treatments for early Alzheimer's disease, but they require biomarker confirmation of amyloid pathology before initiation and have significant safety considerations. 1

FDA-Approved Monoclonal Antibody Infusions

Eligibility Criteria

• Limited to patients with:
  • Mild cognitive impairment (MCI) due to Alzheimer's disease or mild Alzheimer's dementia 1
  • Biomarker-confirmed amyloid pathology via:
    • Positive amyloid PET imaging OR
    • CSF biomarkers indicative of AD (elevated phosphorylated tau and low amyloid beta 42) 1

Available Agents

1. Lecanemab (Leqembi)

   • Received traditional (full) FDA approval in January 2023 1
   • CMS agreed to reimburse when patients are registered in a CMS-approved registry

2. Donanemab (Kisunla)

   • Received traditional FDA approval in July 2024 1

3. Aducanumab (Aduhelm)

   • Received accelerated FDA approval in June 2021 1, 2
   • Development has been discontinued due to limited CMS reimbursement 1
   • Demonstrated dose-dependent reduction in brain amyloid plaques 2, 3

Mechanism of Action

• These monoclonal antibodies target aggregated forms of amyloid-β to reduce amyloid plaque burden 2, 4
• They have shown dose-dependent reduction in markers of Alzheimer's disease pathophysiology 3

Clinical Efficacy

• Aducanumab showed mixed results in phase 3 trials:
  • EMERGE study demonstrated a 22% decrease in clinical decline measured by CDR-SB 3
  • ENGAGE study failed to meet its primary endpoint 3
• Treatment efficacy is most promising when initiated early in the disease course 4

Safety Considerations and Monitoring

ARIA (Amyloid-Related Imaging Abnormalities)

• Most common adverse event with these therapies 3
• Risk factors include:
  • APOE4 genotype (exhibits a gene dose effect) 5
  • Autoimmune or inflammatory conditions 5
  • History of seizures 5
  • Extensive white matter pathology 5

Monitoring Requirements

• MRI monitoring is essential during treatment 5
• For aducanumab, recommended MRI schedule:
  • Before the 5th, 7th, 9th, and 12th infusions 5
  • Additional monitoring for patients with recurrent or serious ARIA 5

Intravenous Immunoglobulin (IVIG)

Unlike monoclonal antibodies, IVIG is not FDA-approved for Alzheimer's disease and has limited supporting evidence:

• The Alzheimer's Association guidelines do not recommend IVIG for routine treatment of Alzheimer's disease 1
• IVIG may be considered in specific cases of infection-related complications but is not a standard treatment for the disease itself 1

Practical Implementation Challenges

Healthcare System Readiness

• The availability of disease-modifying therapies creates demand for timely detection and accurate diagnosis that could overwhelm unprepared healthcare systems 1
• Treatment requires:
  • High proficiency and sufficient resources
  • Close collaboration with comprehensive multi-disciplinary teams 1
  • New models of specialist-primary care collaborations 1

Access and Equity Concerns

• Significant disparities exist in access to diagnosis and treatment 1
• Need for:
  • Tailored practices to improve diversity, inclusion, and equity 1
  • Better access for underrepresented populations in clinical trials 1
  • Addressing workforce shortages, particularly of dementia specialists 1

Emerging Diagnostic Approaches

Blood-Based Biomarkers

• Blood biomarker tests for amyloid pathology are being developed as more accessible alternatives to PET or CSF testing 1
• Recommended performance standards:
  • For triaging: sensitivity ≥90% with specificity ≥85% in primary care 1
  • For confirmatory testing: sensitivity and specificity of ~90% 1

Clinical Decision Algorithm

1. Patient Selection:

   • Identify patients with MCI or mild dementia due to suspected Alzheimer's disease
   • Exclude patients with moderate-to-severe disease (not studied in clinical trials) 4

2. Biomarker Confirmation:

   • Confirm amyloid pathology through either:
     • Amyloid PET imaging
     • CSF biomarkers
     • Validated blood biomarkers (if available) 1

3. Risk Assessment:

   • Perform APOE genotyping to inform risk discussions 5
   • Evaluate for conditions that may increase ARIA risk 5

4. Treatment Initiation:

   • Begin with FDA-approved monoclonal antibody (lecanemab or donanemab)
   • Follow recommended dosing titration schedules 5

5. Monitoring:

   • Regular MRI monitoring for ARIA
   • Ongoing cognitive and functional assessments

Pitfalls and Caveats

• These therapies are not appropriate for patients with moderate or severe Alzheimer's disease 1, 4
• Treatment requires significant infrastructure for administration and monitoring
• Long-term efficacy data remain limited
• Cost and insurance coverage issues may limit access
• Patients and families need thorough education about realistic expectations and potential risks