Risk of Bleeding with Leqembi in ApoE Homozygotes
ApoE ε4 homozygotes have a substantially higher risk of bleeding with Leqembi (lecanemab), with ARIA-H (hemosiderin deposits/microhemorrhages) occurring in 45% of homozygotes compared to 19% in heterozygotes and 13% in non-carriers. 1
ARIA Risk in ApoE ε4 Homozygotes
The FDA label for Leqembi clearly identifies ApoE ε4 homozygote status as a significant risk factor for bleeding complications:
- Symptomatic ARIA-E (brain edema) occurs in 9% of ApoE ε4 homozygotes compared to only 2% of heterozygotes and 1% of non-carriers 1
- Serious ARIA events occur in 3% of ApoE ε4 homozygotes versus approximately 1% of heterozygotes and non-carriers 1
- Overall ARIA incidence (including asymptomatic events) is 45% in ApoE ε4 homozygotes on Leqembi compared to 22% on placebo 1
Bleeding Risk Factors and Complications
The risk of bleeding is further increased by several factors:
- Pre-existing microhemorrhages (≥2) or superficial siderosis at baseline 2
- Concomitant use of anticoagulants significantly increases risk of intracerebral hemorrhage 2, 1
- Fatal cerebral hemorrhage has occurred in patients taking anti-amyloid antibodies with thrombolytic agents 1
In the Clarity AD trial, intracerebral hemorrhage greater than 1 cm in diameter occurred in 0.7% of patients treated with Leqembi compared to 0.1% on placebo. Fatal events of intracerebral hemorrhage have been observed in patients taking Leqembi 1, 3.
Clinical Implications and Monitoring
For ApoE ε4 homozygotes considering Leqembi treatment:
- Testing for ApoE ε4 status should be performed prior to initiation of treatment 1
- More vigilant MRI monitoring is warranted for homozygotes, especially during the first 3-6 months of treatment 2
- ARIA-E generally occurs within 3-6 months of treatment initiation 3
- Patients should be monitored for symptoms including headache, confusion, visual disturbances, dizziness, gait difficulties, nausea, and rarely seizures 2
Treatment Considerations
When considering Leqembi for ApoE ε4 homozygotes:
- The decision should carefully weigh potential benefits against the substantially increased risk of ARIA 2
- Patients requiring anticoagulation should generally not receive Leqembi until more safety data is available 4
- Patients with evidence of cerebral amyloid angiopathy (CAA) are at even higher risk 1
Conclusion
ApoE ε4 homozygotes represent approximately 15% of Alzheimer's disease patients and face a significantly elevated risk of bleeding complications with Leqembi treatment. The risk-benefit assessment must be carefully considered, with special attention to additional risk factors that might further elevate bleeding risk. Regular MRI monitoring and vigilant clinical assessment are essential if treatment is initiated in this high-risk population.