Lecanemab Therapy and APOE Genotype

Excerpt

Lecanemab, brand name Leqembi, is a monoclonal antibody that targets amyloid beta (Aβ) aggregates for the treatment of Alzheimer disease (AD) (1). It is approved by the US Food and Drug Administration (FDA) for individuals with mild cognitive impairment (MCI) or mild dementia stage AD with confirmed amyloid pathology (1). Tests to confirm Aβ pathology in the clinical trials included positron emission tomography (PET) or cerebrospinal fluid (CSF) measurement of the Aβ42/Total Tau ratio (2). This disease-modifying medication is based on the amyloid cascade hypothesis, which suggests Aβ aggregates are a key driver in AD pathogenesis and that the removal of Aβ aggregates should slow cognitive decline.

Lecanemab is associated with amyloid-related imaging abnormalities (ARIA) due to edema (ARIA-E) or hemorrhage (ARIA-H) from blood vessels in the brain (3, 4). Individuals who have one or 2 copies of the AD risk-associated apolipoprotein E (APOE) ε4 (NM_000041.4:c.388T>C) allele have an increased risk of ARIA-E or -H (1) (Table 1). These individuals require additional monitoring during the first year of treatment (5). The FDA-approved label reports that concomitant antithrombotic medication (aspirin, antiplatelet, or anticoagulant) with lecanemab therapy resulted in intracerebral hemorrhage in 2.5% of individuals during clinical trials (1).

The appropriate use recommendations from the Alzheimer’s Disease and Related Disorders Therapeutics Work Group state that individuals requiring anticoagulants should not be treated with lecanemab until additional data regarding this interaction are available (5). Both the FDA-approved label and Alzheimer’s Disease and Related Disorders Therapeutics Work group encourage clinicians to consider participation in a registry for AD treatment to gather additional real-world data on lecanemab therapy (1, 5).