Cerebellar ARIA in a Patient With an APP Duplication Treated With Lecanemab
Darren Gitelman1, Jorge Llibre Guerra2, Eric McDade2, Lon Schneider3, Tammie Benzinger2, William Kreisl4, Randall Bateman2, David Clifford2
1Behavioral Neurology, Advocate Health, 2Washington Univ School of Medicine, 3USC School of Medicine, 4Eisai Co. Ltd.
Objective:
Case report of serious cerebellar ARIA in a participant with an APP gene duplication in the DIAN-TU-001 study receiving lecanemab.
Background:
Treatment with β-amyloid targeting antibodies (βATAs) carry a risk for amyloid related imaging abnormalities (ARIA) with either edema / effusion (ARIA-E) or hemorrhage (ARIA-H). Risks for ARIA include Apolipoprotein E ε4 and cerebral amyloid angiopathy (CAA). ARIA-E is usually reported in the cerebral cortex, but rarely in the cerebellum. βATAs have been studied in sporadic AD, but less so in Dominantly Inherited Alzheimer’s Disease.
Design/Methods:
DIAN-TU-001 is a placebo-controlled, double-blind Phase II/III study evaluating the efficacy and safety of E2814 (antibody against the microtubule binding region of tau), administered alone or concurrently with lecanemab. Participants in DIAN-TU-001 all have mutations in the APP, PSEN1 or PSEN2 genes. This participant was in the symptomatic cohort (CDR=0.5–1) and was to receive open-label lecanemab followed by double-blind E2814.
Results:
Participant genetics: APP gene duplication and ApoE ε3/ε3. Baseline MRI: 1 microhemorrhage each: right cerebellum and left insula. After the 4th infusion, a safety MRI showed widespread ARIA-E of the cerebellum and microhemorrhages in the cerebellum (7) and right occipital lobe (1). Cerebellar expansion caused a mild obstructive hydrocephalus, but a shunt was not needed. Treatment included high dose IV dexamethasone, and a tapering outpatient course of oral dexamethasone.
In the phase 3 study of lecanemab in early sporadic AD (CLARITY-AD) of 898 subjects treated with lecanemab, 3 (0.33%) had ARIA-E in the cerebellum, as an extension of occipital ARIA-E. There were no concurrent cerebellar signs and all resolved within 2 months.
Conclusions:
Cerebellar ARIA from βATAs is uncommon in sporadic AD. This subject’s serious cerebellar ARIA-E/H may relate to an APP duplication, and possible evidence of CAA (microhemorrhage). βATA use in patients with similar genotypes or Down’s syndrome should be approached carefully.
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