APOE ‐guided lecanemab dosing dissociates ARIA‐E from ARIA‐H: The K‐ROAD study

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INTRODUCTION: We evaluated whether apolipoprotein E (APOE εε4) genotype-guided lecanemab escalation mitigates the APOE εε4-driven amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) gradient and whether ARIA-E and ARIA with hemosiderin deposition (ARIA-H) are mechanistically distinct. METHODS: Five hundred eight patients with early Alzheimer's disease received APOE genotype-guided lecanemab escalation (target maximum plasma concentration [Cmax] thresholds: 118, 308, and 404 µg/mL for εε4/εε4, heterozygote, and non-carrier) across eight Korean centers, with magnetic resonance imaging-based ARIA surveillance. RESULTS: ARIA-E incidence was 2.0% in non-carriers and 6.2% in εε4/εε4 homozygotes (εε4/εε4-versus-non-carrier OR 3.25, versus 8.49 in Clarity AD and 8.32 in Japan post-marketing surveillance). Any ARIA-H was independently predicted by baseline cerebral microbleeds, white matter hyperintensity (WMH), age, and APOE εε4 allele dose (aORs 1.23, 1.50, 1.04, 1.75). DISCUSSION: Under genotype-guided escalation, observations are compatible with - but do not establish - attenuation of the APOE εε4-driven ARIA-E gradient, whereas ARIA-H risk reflected baseline cerebrovascular burden. These findings raise the hypothesis of a dual-axis safety framework requiring randomized confirmation.

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