Clinical implementation of fluid biomarkers and APOE test in an era of disease modifying therapy for dementia

Abstract

Lecanemab, an anti–amyloid–β (Aβ) antibody, has been shown to remove Aβ plaques substantially from the brain of Alzheimer disease (AD) patients in a phase 3 clinical trial. Based on its clinical benefit, Lecanemab was approved for treatment of AD in Japan. The role of biomarkers in clinical practice has been dramatically changed by the introduction of disease–modifying therapy such as Lecanemab. In order to identify appropriate patients for the use of Lecanemab, “amyloid–β test” is required to confirm Aβ pathology in the brain either by cerebrospinal fluid (CSF) testing or amyloid PET scan. Early stage of AD including mild cognitive impairment (MCI) and mild dementia is a target of Lecanemab treatment. Biomarker tests for those population have become more important. Specialists for dementia practice are expected to play a major role for establishing amyloid–β testing system throughout Japan, which facilitates an efficient diagnostic pathway for the use of lecanemab. With the advent of disease–modifying therapy, the clinical significance of APOE testing should be reconsidered. The incidence of amyloid–related imaging abnormalities (ARIA), which may occur as an adverse event of anti–amyloid–β antibody therapy, is largely influenced by APOE genotypes. Symptomatic ARIA is most frequently observed in patients with APOE ε4 homozygotes, followed by ε4 heterozygotes and ε4 non–carriers. The U.S. FDA has issued a warning about ARIA in the label of lecanemab, and announced that APOE testing should be performed in prior to the use of lecanemab. The clinical significance of APOE testing and its appropriate use in the era of disease–modifying therapy are discussed.