Prevalence of Cerebral Microhemorrhages and Cortical Superficial Siderosis in APOE4/4 Homozygotes with Early Alzheimer’s disease: Baseline Findings from Phase 3 Trial of Oral ALZ‐801 in APOE4/4 Homozygotes (APOLLOE4)

Abstract

AbstractBackgroundPlaque clearing amyloid antibodies show an increased risk of amyloid‐related imaging abnormalities with edema or hemorrhages (ARIA‐E or ARIA‐H). ARIA risk increases with number of APOE4 alleles, with APOE4/4 homozygotes showing the highest risk related to high burden of Aβ plaque in microvessels (cerebral amyloid angiopathy, CAA). To decrease the risk of ARIA, amyloid antibody trials exclude subjects with CAA‐related lesions such as >4 microhemorrhages (MH) or superficial siderosis. ALZ‐801 (valiltramiprosate), an oral drug that inhibits formation of neurotoxic Aβ oligomers, shows promising efficacy in APOE4 carriers with no observed ARIA‐E (Abushakra 2017, 2022). Two ALZ‐801 trials are currently ongoing in APOE4 carriers with Early AD. A Phase 2 study enrolled APOE4 carriers, and a Phase 3 trial enrolled APOE4/4 patients. Both studies allow >10 MH and/or some siderosis lesions at baseline.MethodThe fully‐enrolled Phase 3 trial (APOLLOE4) included 325 homozygotes with Early AD (MMSE ≥22). We evaluated prevalence of microhemorrhages (MH), macrohemorrhages and superificial siderosis (CAA lesions). Baseline MRIs acquired from 1.5T/3T scanners were centrally evaluated by Clario, and the number/location of these CAA lesions is reported.ResultSubjects had mean age 69 years, 51% female, MMSE 26, 82% white, 65% with MCI. Of 325 subjects, 313 had baseline MRIs that showed > 1 MH in 32%, including 9% with > 4 MH. A total of 9% had ≥ 1 superficial siderosis, and 2 subjects had macrohemorrahages. Occipital and frontal lobes were most common locations of CAA lesions. Most subjects had white matter disease (Fazekas = 1).ConclusionAPOE4/4 homozygotes show high prevalence of CAA lesions with 32% and 9% having lobar microhemorrhages and superificial siderosis respectively. This high burden of CAA lesions most likely underlies the high incidence of ARIA in APOE4/4 patients treated with the approved amyloid antibodies (30%‐60%). ARIA‐E is also reported in APOE4/4 patients treated with placebo in lecanemab & gantenerumab trials (4%‐6%). This background ARIA likely reflects spontaneous CAA‐related inflammation commonly reported in APOE4 carriers (CAA‐RI, Regendhardt 2020). Oral ALZ‐801 in the ongoing studies has not shown increased ARIA risk, and has safety advantage over amyloid antibodies especially for APOE4/4 homozygous patients.