Anti-Amyloid Monoclonal Antibodies in Early Alzheimer Disease: Lecanemab and Donanemab.

Abstract

Background/objectives: Alzheimer disease (AD) causes progressive cognitive and functional loss and substantial caregiver and healthcare burden. Anti-amyloid monoclonal antibodies represent a shift toward biology-directed treatment in biomarker-confirmed early symptomatic AD, but modest clinical effects must be balanced against amyloid-related imaging abnormalities (ARIA), intensive monitoring, and implementation burden. Heterogeneity in trial populations, endpoints, dosing, stopping rules, and follow-up complicates interpretation. This narrative review critically integrates efficacy, safety, durability, biomarker, and implementation evidence for lecanemab and donanemab while preserving study-family relationships and avoiding unsupported cross-trial superiority claims.

Methods: For this revised narrative review, a targeted PubMed/MEDLINE search covering the period from database inception was initially conducted before manuscript submission and was subsequently updated through 21 August 2026, supplemented by reference-list and citation tracking. Search terms combined Alzheimer disease with lecanemab, donanemab, anti-amyloid monoclonal antibody, ARIA, APOE, amyloid PET, open-label extension, real-world, clinical meaningfulness, implementation, and access. Sixty-two sources were purposively selected for a comprehensive narrative synthesis; no meta-analysis or formal certainty grading was performed.

Results: Pivotal trials demonstrated statistically significant but modest average slowing of decline: Clarity AD showed a 0.45-point between-group difference in CDR-SB worsening at 18 months, and TRAILBLAZER-ALZ 2 showed a 3.25-point iADRS difference in the low/medium-tau population at 76 weeks. ARIA-E occurred in 12.6% of lecanemab-treated and 24.0% of donanemab-treated participants in the pivotal trials, with higher risk in APOE ε4 carriers. Extensions and biomarker analyses suggest persistent biological effects but are less secure for causal inference, and real-world evidence is currently more mature for lecanemab.

Conclusions: Both antibodies substantially reduce amyloid and modestly slow average clinical decline in selected patients, but neither restores lost function, greater amyloid clearance does not establish greater individual benefit, and cross-trial superiority cannot be inferred. Treatment requires biomarker-guided selection, APOE-informed risk counseling, serial MRI, infusion and ARIA-management capacity, and shared decision-making that incorporates cost, access, and patient/caregiver burden.