From the Guidelines
Leqembi can be used in APOE4 heterozygotes, but with close monitoring due to the increased risk of amyloid-related imaging abnormalities (ARIA). The presence of the Apolipoprotein E ε4 allele is a significant risk factor for the development of ARIA-E, with 7.1% of x/ε4 heterozygotes developing ARIA-E in the Phase II double-blind study 1. However, this risk does not necessarily preclude the use of Leqembi in APOE4 heterozygotes.
Key Considerations
- APOE4 carriers, including heterozygotes, have an increased risk of ARIA, which includes ARIA-E (edema) and ARIA-H (microhemorrhages and superficial siderosis) 1.
- Patients should undergo genetic testing for APOE status before starting treatment, and those with the APOE4 allele should be monitored more closely with more frequent MRI scans during treatment.
- The standard dosing regimen for Leqembi is 10 mg/kg administered as an intravenous infusion every two weeks, regardless of APOE status.
Monitoring and Management
- Close monitoring of APOE4 heterozygotes is crucial to minimize the risk of ARIA and ensure timely intervention if necessary.
- More frequent MRI scans should be performed during treatment to detect any potential ARIA-related changes.
- The benefit-risk profile of Leqembi treatment in APOE4 heterozygotes should be carefully evaluated, taking into account the individual patient's risk factors and medical history.
From the FDA Drug Label
Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results Prescribers should inform patients that if genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA [see Warnings and Precautions (5. 1)]. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on LEQEMBI vs. 22% on placebo) than in heterozygotes (19% on LEQEMBI vs 9% on placebo) and noncarriers (13% on LEQEMBI vs 4% on placebo) Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared to 2% of heterozygotes and 1% noncarriers.
Lequembi can be used in APOE4 heterozygotes. However, the incidence of ARIA is higher in ApoE ε4 heterozygotes (19% on LEQEMBI) compared to noncarriers (13% on LEQEMBI). The risk of ARIA should be considered when deciding to initiate treatment with LEQEMBI in APOE4 heterozygotes 2 2.
From the Research
Lecanemab Use in APOE4 Heterozygotes
- The use of lecanemab in APOE4 heterozygotes is a topic of interest, given the higher risk of amyloid-related imaging abnormalities (ARIA) in APOE4 carriers 3, 4.
- According to the Appropriate Use Recommendations (AURs) for lecanemab, APOE genotyping is recommended to better inform risk discussions with patients who are lecanemab candidates, especially APOE4 homozygotes 3.
- However, the AURs do not specifically address the use of lecanemab in APOE4 heterozygotes, and the safety and efficacy of lecanemab in this population are not well established 3.
- A study published in The New England Journal of Medicine found that lecanemab did not slow cognitive decline in APOE4 carriers, and actually enhanced the decline in study participants with two APOE4 genes 5, 6.
- Another study published in Alzheimer's Research & Therapy found that ARIA-E was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%) 4.
Safety and Efficacy Considerations
- Lecanemab has been shown to be generally well-tolerated, but with risks including an increased rate of ARIA and infusion reactions relative to placebo 4, 6.
- The most common adverse events in the lecanemab group (> 10%) were infusion-related reactions, ARIA with hemosiderin deposits (ARIA-H) microhemorrhages, COVID-19, ARIA with edema (ARIA-E), and headache 4.
- Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care 4.