Issues to Discuss with Patients Considering Lecanemab
Lecanemab offers modest clinical benefit (27% slowing of decline) but carries significant risks including brain swelling (12.6%), brain bleeding (15-20%), and potential death—requiring extensive monitoring and careful patient selection. 1, 2
1. Clinical Benefits (What to Expect)
Magnitude of Benefit:
- 27% reduction in clinical decline at 18 months on the CDR-SB scale (primary outcome measure) 1
- 26% reduction in cognitive decline on ADAS-Cog14 (memory and thinking tests) 1
- 37% reduction in functional decline on ADCS-MCI-ADL (daily activities) 1
- 49-56% less decline in quality of life measures, with 38% less caregiver burden 3
Important Caveat: The absolute benefit is small—the difference between treatment and placebo was 0.45 points on the CDR-SB scale at 18 months, which may not be perceptible to many patients and caregivers 4. Some experts question whether this meets the threshold for clinically meaningful improvement 4.
Treatment Effect Over Time: Benefits appeared starting at 6 months and continued through 18 months, suggesting potential for disease modification rather than just symptom management 1, 5
2. Major Safety Risks
Brain Swelling (ARIA-E):
- Occurs in 12.6% of patients receiving lecanemab 6, 1
- Most cases are asymptomatic but serious and life-threatening events can occur 1
- ARIA can be fatal 1
- Typically occurs within the first 3-6 months of treatment 6
Symptoms to watch for (if ARIA-E becomes symptomatic):
- Headache, confusion, dizziness, vision changes, nausea, difficulty walking, seizures 1
Brain Bleeding (ARIA-H):
- Occurs in 15-20% of patients in clinical trials 7, 6
- Includes small microhemorrhages and superficial siderosis 7
- Serious intracerebral hemorrhages >1 cm have occurred, some fatal 1
Genetic Risk Factor (APOE ε4):
- APOE ε4 homozygotes (15% of AD patients) have significantly higher ARIA risk 1, 2
- These patients experience more symptomatic, serious, and severe ARIA compared to non-carriers 1
- Genetic testing should be performed before starting treatment to inform risk discussion 1, 2
- Patients can still receive treatment without genetic testing, but their risk level cannot be determined 1
Other Adverse Events:
- Infusion-related reactions (flu-like symptoms, nausea, vomiting, blood pressure changes), most common with first infusion 1
- Hypersensitivity reactions including angioedema and anaphylaxis 1
3. Treatment Requirements and Burden
Infusion Schedule:
- Intravenous infusion every 2 weeks for 18 months (approximately one hour per infusion) 1
- After 18 months, may continue every 2 weeks or transition to monthly maintenance dosing 1
- Must be administered in a facility equipped to manage infusion reactions 6
Mandatory MRI Monitoring:
- Baseline brain MRI required within 12 months before starting treatment 7, 8, 1
- Follow-up MRIs required before the 5th, 7th, and 14th infusions 7, 6, 1
- Additional MRIs needed if symptoms suggestive of ARIA develop 1
- MRI must include specific sequences: T2 FLAIR, T2* GRE or SWI, and DWI 7
- 3T MRI provides greater sensitivity for detecting microhemorrhages 7
Biomarker Confirmation Required:
- Amyloid pathology must be confirmed before starting treatment through amyloid PET scan, CSF biomarkers, or blood-based biomarkers (plasma p-tau217) 6, 9, 1
- Blood-based biomarkers offer advantages in accessibility and cost (AUC 0.92-0.98 for predicting amyloid status) 6, 9
4. Absolute Contraindications (Cannot Receive Treatment)
MRI Exclusionary Findings: 7, 8, 6
- Intraparenchymal macrohemorrhages >10 mm diameter
- 4 or more microhemorrhages <10 mm diameter
- Superficial siderosis
- Vasogenic edema
- Significant white matter hyperintensities
- Multiple lacunar infarcts
- Major vascular territory infarcts
- Evidence of cerebral amyloid angiopathy-related inflammation (CAA-ri)
- Brain tumors (except meningiomas or arachnoid cysts)
- CNS infection
- Aneurysms and vascular malformations
Medication Interactions:
- Anticoagulants significantly increase bleeding risk—the appropriate use recommendations suggest patients requiring anticoagulants should not receive lecanemab until more safety data are available 2
- Antithrombotic medications increase risk of brain bleeding 1
5. Eligibility Criteria
Who Can Receive Treatment: 7, 6, 1
- Mild cognitive impairment (MCI) due to Alzheimer's disease OR mild dementia stage
- Confirmed amyloid pathology in the brain
- No exclusionary MRI findings (see above)
Who Should NOT Receive Treatment:
- Patients with moderate or severe dementia (treatment only studied in early-stage disease) 1
- Patients with exclusionary MRI findings 7, 8
- Patients requiring anticoagulation 2
6. Access and Cost Considerations
Insurance Coverage:
- Medicare requires enrollment in a CMS-approved patient registry for reimbursement 7, 6
- Medication cost is $26,500 per year 4
- Total cost of care includes infusions, MRI monitoring, biomarker testing, and management of adverse events 4, 10
Healthcare System Requirements:
- Treatment requires multidisciplinary teams with specialized training in monoclonal antibody therapy and ARIA management 7, 6, 10
- Access to emergency MRI and neurology consultation is essential 6
- Too few dementia specialists are currently available to meet potential demand, creating access barriers particularly for underserved populations 7, 6
7. Special Populations and Equity Concerns
- Clinical trials included approximately 20% non-White individuals, limiting generalizability to diverse populations 6
- Trial participants were younger (mean age 71 years) than typical real-world patients with mild AD (mean age 85 years), and bleeding risk increases with age 4
- APOE ε4 homozygotes (15% of trial population) did not show treatment effect on the primary endpoint (CDR-SB), though effects were seen on secondary endpoints and biomarkers 1
8. Comparison to Existing Treatments
- Lecanemab's cognitive effect may be smaller than cholinesterase inhibitors (donepezil), which cost approximately 100 times less 4
- Unlike cholinesterase inhibitors that provide symptomatic relief, lecanemab targets underlying amyloid pathology and may offer disease-modifying effects 5
- Long-term benefits beyond 18 months are unknown—the argument that greater benefit will accrue over time is plausible but lacks evidence 4
9. Monitoring and Management During Treatment
If ARIA-E Develops:
- Asymptomatic mild ARIA-E: May continue dosing 1
- Asymptomatic moderate or severe ARIA-E: Suspend dosing until radiographic resolution 1
- Symptomatic ARIA-E (any severity): Suspend dosing until symptoms resolve and MRI shows resolution 1
- Follow-up MRI 2-4 months after initial identification to assess resolution 1
If ARIA-H Develops:
- Asymptomatic mild ARIA-H: May continue dosing 1
- Asymptomatic moderate or severe ARIA-H: Suspend dosing 1
- Any symptomatic ARIA-H: Suspend dosing 1
Critical Safety Consideration:
- ARIA-E symptoms can mimic ischemic stroke—clinicians must consider ARIA-E before administering thrombolytic therapy to patients on lecanemab 1
- Patients should carry information that they are being treated with lecanemab 1
10. Decision-Making Framework
Patients most likely to benefit:
- Early-stage disease (MCI or mild dementia)
- Confirmed amyloid pathology
- No exclusionary MRI findings
- Not requiring anticoagulation
- Able to commit to biweekly infusions and frequent MRI monitoring
- Understanding and acceptance of modest benefit and significant risks
Patients who should avoid treatment:
- Moderate-to-severe dementia
- Multiple vascular risk factors or prior strokes
- Need for anticoagulation
- Unable to undergo frequent MRI monitoring
- APOE ε4 homozygotes should have detailed risk-benefit discussion given higher ARIA risk and uncertain efficacy 1
Key Discussion Points:
- The benefit is real but modest—approximately 5 months less decline over 18 months 1
- Serious risks exist, including potentially fatal brain swelling and bleeding 1
- Extensive monitoring is required (multiple MRIs, biweekly infusions) 1, 10
- Long-term benefits beyond 18 months are unknown 4
- Cost is substantial and may not be covered without registry enrollment 7, 6, 4