To evaluate prevalence of amyloid-related imaging abnormalities (ARIA) in APOE4/4 homozygotes with Early Alzheimer’s disease (AD), including microhemorrhages and siderosis or vasogenic edema (ARIA-H or ARIA-E).

APOE4 carriers show increased risk of ARIA in AD trials with amyloid-clearing antibodies, the highest in APOE4/4 homozygotes, related to a high burden of aggregated beta amyloid in cerebral microvessels (cerebral amyloid angiopathy, CAA). Trials with amyloid-clearing antibodies exclude subjects with cortical superficial siderosis or >4 microhemorrhages (MH). ALZ-801 (valiltramiprosate) is an oral, highly brain-penetrant inhibitor of formation of soluble neurotoxic amyloid oligomers, which showed promising efficacy in APOE4 carriers with no observed ARIA-E (Abushakra 2016). Two ongoing trials with ALZ-801 focus on APOE4 carriers with Early AD:  Phase 2 enrolled APOE3/4 or APOE4/4, and APOLLOE4 Phase 3 is enrolling only APOE4/4; both studies allow subjects with any number of MH or siderosis.

Baseline MRIs were from Phase 2 and 3 studies (MCI or Mild AD, MMSE ≥22), acquired from 1.5T or 3T scanners and centrally evaluated. We report the type and number of ARIA-E/H lesions as of August 2022.

Baseline demographics of the two studies were similar (~50% female, age 69 years, MMSE 25-26). In 242 homozygotes (211 from Phase 3) there were no subjects with ARIA-E, 72 with any MH, 23 with >4 MHs, of whom 15 had >10 MHs, 2 had macrohemorrhages >1 cm, and 20 had superficial siderosis lesions.

APOE4/4 homozygotes show a high incidence and wide range of CAA-related lesions at the baseline of ALZ-801 studies. Many of these subjects are excluded from amyloid immunotherapy trials due to increased risk of ARIA. ALZ-801 studies include MRI monitoring with 4 scans over 78 weeks of treatment. The favorable ALZ-801 safety profile may provide a treatment alternative for APOE4 carriers at high risk of symptomatic ARIA.