Phase 3 Trials of Aducanumab Highlight High Risk of Amyloid-Related Imaging Abnormalities in APOE Carriers

Christopher D. Whelan, PhD

Newly published in Neurology, a genome-wide association study (GWAS) of the phase 3 ENGAGE (NCT02477800) and EMERGE (NCT02484547) trials of aducanumab (Aduhelm; Biogen) revealed a strong, significant link between apolipoprotein (APOE) carrier status and the risk of amyloid-related imaging abnormalities (ARIA). Overall, the research highlights the value genetics add to guiding clinical treatment decisions and the importance of reporting heterozygosity by genotype, given the substantially larger effects observed among ε4 homozygotes vs heterozygotes.¹

Led by senior investigator Christopher D. Whelan, PhD, a senior scientist in the Translational Biology Research Group at Biogen, the analysis included 1691 of the 3285 participants from the intent-to-treat population of the phase 3 studies. Of these, 529 (31%) had ARIA-edema, 324 (19%) had ARIA-H microhemorrhage, 229 (14%) had ARIA-H superficial siderosis, and 1047 experienced none of these events. Sex was evenly split across ARIA-E and ARIA-H microhemorrhage; however, of those who experienced ARIA-H superficial siderosis, 40% were female.

The sample observed had a mean age of 70.3 years, with all participants of European ancestry. When compared with ε3/ε3 homozygotes, results showed a dose-dependent association between APOE ε4/ε4 and ARIA. All told, participants homozygous for APOE ε4 exhibited 4.28 greater odds of experiencing AIRA-H, 4.58 greater odds of experiencing ARIA-H microhemorrhage, and 7.84 greater odds of experiencing ARIA-H superficial siderosis. Notably, there was a less pronounced effect of carrying 1 copy of the ε4 allele (ε2/ε4 or ε3/ε4) in ARIA-E (OR, 1.74-2.60), ARIA-H microhemorrhage (OR, 1.46-1.63), and ARIA-H superficial siderosis (OR, 2.64-3.14).

"ARIA represents the most common adverse event for aducanumab, and APOE genotype provides a useful indication of ARIA risk,” the study authors wrote.¹ "Although not yet standard in clinical settings, targeted genotyping of APOE is relatively inexpensive, highly accurate, and consistent over time, making it an attractive biomarker for patient risk stratification."

Additional data from the study showed no evidence of a neuroprotective effect of APOE ε2 when assessed in a small group of ε2/ε3 carriers (n = 36; P = 0.12-0.69). This was notable considering previous research has shown that APOE ε2 is the only replicated variant associated with longevity. Furthermore, APOE ε2 has been robustly associated with reduced risk of clinically diagnosed AD and reductions in amyloid plaque and tau Braak stage in neuropathological studies.²

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Continued stratification of the effect of APOE on the risk of ARIA showed that APOE ε4/ε4 genotypes were significantly associated with mild, moderate, and severe radiographic ARIA. The effect was stronger among ε4/ε4 homozygotes than ε3/ε4 heterozygotes and showed a larger effect in severe (ε4/ε4 OR, 7.04–24.64; P ≤ 2.38 × 10−6) vs mild (ε4/ε4 OR, 3.19–5.00; P ≤ 1.37 × 10−5) cases. Despite APOE being associated with both symptomatic and asymptomatic ARIA, no association was seen for APOE when comparing symptomatic vs asymptomatic cases (P >.05).

Overall, investigators failed to find a significant association between APOE and isolated ARIA-H either microhemorrhage or superficial siderosis, although sample sizes were small and analyses were underpowered. After controlling for the APOE locus, there was no additional genome-wide significant associations with ARIA independent of the APOE region. Notably, gene-based testing showed no additional significant signals associated with the ARIA traits.

Using a polygenic risk score analysis, investigators documented a significant association between increased polygenic risk of AD and all 3 types of ARIA (ARIA-E: beta = 0.14, P = 0.04; ARIA-H microhemorrhage: beta = 0.20, P = 0.01; ARIA-H with superficial siderosis beta = 0.20, P = 0.03).

The study was limited by the fact that the number of copies of ε4 was not a stratification factor, leaving potential for imbalance across planned dose groups. In addition, the estimated odds ratios for certain events may have been sensitive to the small number of events in the ε3/ε3 reference group. Lastly, the study featured only those with European ancestry in the US, Europe, Canada, and Australia, and thus, the results may not be generalizable to other regions or ancestorial groups.

REFERENCES
1. Loomis SJ, Miller R, Castrillo-Viguera C, et al. Genome-wide association studies of ARIA from the Aducanumab phase 3 ENGAGE and EMERGE studies. Neurology. 2024;102(3). doi:10.1212/WNL.00000000000207919
2. Kim Y, Devanand DP, Carlson S, Goldberg TE. Apolipoprotein E genotype e2: neuroprotection and its limits. Front Aging Neurosci. 2022;14:919712. doi:10.3389/fnagi.2022.919712