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How does lecanemab differ from aducanumab in clinical outcomes and mechanism?
Executive Summary
Lecanemab and aducanumab are both anti–amyloid-β monoclonal antibodies approved to treat early Alzheimer’s disease, but they differ in molecular target selectivity, clinical timing of effects, and observed safety patterns. Lecanemab preferentially binds toxic protofibrils and shows faster amyloid clearance with clinical benefit emerging within months, while aducanumab binds more to fibrillar plaques and has a slower time course and a more contested clinical signal; real‑world adverse‑event reports and mechanistic studies report overlapping but distinct patterns of amyloid‑related imaging abnormalities and other signals [1] [2] [3] [4]. Below I extract the key claims from the supplied analyses, compare evidence and dates, and highlight where data agree, diverge, or remain incomplete.
1. Why the molecular target matters — protofibrils versus plaques and what that implies
Lecanemab’s defining claim is high affinity for amyloid‑β protofibrils (oligomeric intermediates) and much lower binding to monomers and fibrils, a profile reported to give 10–15x selectivity versus fibrils and >1000‑fold versus monomers, which is argued to focus activity on the most neurotoxic species and spare some plaque‑associated vascular effects [2]. Mechanistic investigations published January 2025 and earlier propose that lecanemab’s binding to protofibrils correlates with cerebrospinal‑fluid protofibril measures and biomarkers of neurodegeneration such as tau and neurogranin, suggesting a plausible pathway for slowing progression [1]. By contrast, aducanumab preferentially targets highly aggregated, fibrillar Aβ in plaques; its clearance of plaque material is well documented, but the linkage to clinical benefit was more contested during regulatory review and post‑approval debate [5] [6]. These differing targets create distinct expectations for onset of effect and vascular interactions.
2. Clinical timing and outcomes — rapid clearance versus contested benefit
The supplied analyses report faster biochemical and clinical timelines for lecanemab: amyloid reductions within roughly three months and measurable clinical slowing by six months in trial data summaries, versus aducanumab’s plaque reductions often documented over ~18 months and more mixed claims of clinical benefit [3]. Lecanemab’s randomized trials that underpinned FDA approval showed a statistically significant slowing of cognitive decline in early disease, and follow‑up mechanistic work supports an on‑target effect on protofibrils [1] [2]. Aducanumab’s history is different: accelerated approval in 2021 rested on surrogate plaque reductions with disputed clinical benefit, leading to regulatory controversy and later corporate reprioritization away from commercial development [5] [6]. The head‑to‑head comparative efficacy remains indirect because no randomized trial directly comparing the two agents has been reported in the provided materials.
3. Safety signals — shared risks but different patterns and onset
Both agents are associated with amyloid‑related imaging abnormalities (ARIA), including microhemorrhages and edema, and infusion‑related reactions; however, the balance of ARIA‑E (edema) versus ARIA‑H (microbleeds), incidence, and timing differ in the datasets. Lecanemab’s trial and mechanistic literature and adverse‑event analyses report a lower incidence of ARIA‑E compared with some prior antibodies and a shorter median time‑to‑onset of reported adverse events in FDA spontaneous reports (median 33 days for lecanemab versus 146 days for aducanumab in a May 2025 disproportionality analysis) [4] [7] [8]. The same pharmacovigilance analysis flagged unusual preferred terms not on labels (e.g., “feeling cold,” “screaming,” encephalitis for lecanemab; skin and breast cancer reports for aducanumab), but these signal‑detection outputs require careful causality assessment and can reflect reporting biases [4] [7]. APOE ε4 genotype‑related risk was emphasized for aducanumab in prior literature, and vigilance for genotype interactions applies to both drugs [9] [5].
4. Conflicting interpretations and corporate/regulatory context that shape the record
The evidence corpus shows competing narratives: sponsors and some trial reports emphasize lecanemab’s protofibril targeting and clinical benefit with faster onset and potentially fewer ARIA‑E events [2] [1], while documentation about aducanumab highlights robust plaque removal but a controversial clinical efficacy claim and higher profile regulatory dispute [5] [6]. Post‑marketing pharmacovigilance studies from 2025 that mine FDA reports suggest similar adverse‑event profiles overall but different time courses and unexpected signals, underscoring that spontaneous report databases mix reporting rate effects, market exposure, and surveillance intensity [4] [7]. Biogen’s deprioritization of aducanumab and divergent regulatory decisions in the EU and US are part of the background that shaped both clinical uptake and the observational record [5].
5. What remains unresolved and where further evidence is most needed
Critical gaps persist: no randomized head‑to‑head trial between lecanemab and aducanumab is provided here, so comparisons rely on mechanism, trial designs, and indirect real‑world signals [3] [2] [5]. Long‑term outcomes, genotype‑specific risk‑benefit ratios, reproducibility of the unusual adverse‑event signals from pharmacovigilance, and mechanistic confirmation that protofibril targeting yields sustained functional benefit require further study; available studies through 2025 provide promising mechanistic correlation for lecanemab but cannot fully resolve relative clinical superiority [1] [4] [3]. Clinicians and patients should weigh target selectivity, rate of amyloid removal, ARIA risk profile, and the strength of clinical‑outcome evidence when choosing or interpreting these therapies.