Donanemab in the Treatment of Alzheimer’s Disease: A Comprehensive Review

Donanemab is a novel investigational monoclonal antibody developed by Eli Lilly, targeting pyroglutamate-modified amyloid-β (Aβ) plaques, a hallmark of Alzheimer’s disease (AD). It represents one of the most promising disease-modifying therapies for early symptomatic AD. This review explores Donanemab’s mechanism of action, preclinical and clinical trial outcomes, efficacy, safety profile, and its position in the evolving therapeutic landscape of AD. Donanemab (Kisunla) is a humanized Immunoglobulin (Ig) G1 monoclonal antibody targeting a neoepitope of Aβ peptide in AD. It binds N-terminally truncated, pyroglutamate-modified Aβ species in plaque cores, enabling microglial clearance of senile plaques and slowing clinical decline. In recent trials (TRAILBLAZER-ALZ 1 and 2), Donanemab achieved rapid and profound reductions in brain Aβ burden (∼40%–60% Centiloid reduction by 24–76 weeks) and stabilized cognition relative to placebo, especially in patients with lower baseline tau. Its pharmacokinetics (PK) reflect typical IgG1 behavior (half-life is about 10–12 days, dose-proportional exposure) but is complicated by frequent anti-drug antibodies. Major safety concerns are amyloid-related imaging abnormalities, occurring in approximately 20%–30% of treated patients (often asymptomatic). Recommended dosing begins with 700 mg Intravenous × 3 doses then 1400 mg monthly, with positron emission tomography-based rules for discontinuation. This review summarizes AD pathology and epidemiology, Donanemab’s discovery and molecular properties, structure – activity considerations, PK/pharmacodynamics profile, clinical efficacy/safety data, therapeutic monitoring methods, and future challenges.