Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials

Background Donanemab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has shown the ability to reduce cerebral amyloid burden in early Alzheimer's disease (AD). However, uncertainties remain regarding its clinical relevance, particularly in relation to tau pathology, APOE ε4 genotype, and methodological limitations in existing trials. Objective To conduct a systematic review and exploratory meta-analysis to evaluate the efficacy, safety, and tolerability of donanemab in patients with mild to moderate AD. Methods We conducted a systematic review and exploratory meta-analysis following PRISMA guidelines. Randomized controlled trials comparing donanemab to placebo in individuals aged ≥65 years with biomarker-confirmed mild to moderate AD were included. Outcomes included cognitive measures (ADAS-Cog13, MMSE, CDR-SB, iADRS, ADCS-iADL) and adverse events (ARIA-E, ARIA-H, infusion reactions, discontinuations). Random-effects models were used to estimate pooled mean difference (MD) or risk ratio (RR) with 95% confidence intervals. Subgroup analyses were performed by baseline tau burden and APOE ε4 genotype. Results Three trials (n = 2054) were included. Donanemab modestly reduced cognitive decline compared to placebo: ADAS-Cog13 (MD, −1.86), CDR-SB (MD, −0.36), MMSE (MD, 0.64), and iADRS (MD, 3.19), with similar effects across tau subgroups. The risk of ARIA-E was markedly increased (RR, 12.39), especially among APOE ε4 homozygotes. Infusion reactions (RR, 11.90) and discontinuations (RR, 3.22) were also more frequent. Conclusions Donanemab demonstrated modest cognitive benefits, the clinical significance of which remains uncertain. Independent, longer-term trials with rigorous methodology and active comparators are warranted to more clearly define its therapeutic value in the treatment of AD.