APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials

Abstract

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid-targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid-positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non-carriers. Carrier and non-carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS-Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non-carriers to amyloid-targeting therapies and similar or less disease progression with placebo in amyloid-positive trials. HIGHLIGHTS: Amyloid-targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers. Clinical decline is the same/slightly faster in amyloid-positive APOE ε4 non-carriers. Prevalence of non-carriers in trial populations could impact outcomes.