How do anti‑amyloid monoclonal antibodies differ in mechanism, efficacy, and safety (lecanemab vs donanemab vs aducanumab)?
Executive summary
Anti‑amyloid monoclonal antibodies differ in what forms of Aβ they bind, how much they lower brain amyloid and downstream biomarkers, and in clinical benefit versus risk balance: lecanemab targets soluble protofibrils with strong plaque‑clearing and modest cognitive benefit shown in CLARITY‑AD, donanemab targets modified deposited plaques with some larger cognitive signal in subgroup analyses, and aducanumab principally cleared plaques with controversial and smaller clinical effects; all three increase amyloid‑related imaging abnormalities (ARIA) but with differing reported rates [1] [2] [3] [4].
1. Mechanisms — which Aβ species each antibody prefers and why that matters
Lecanemab is a humanized IgG1 engineered from mAb158 with high affinity for soluble Aβ protofibrils (reportedly far greater than aducanumab for protofibrils), which explains its pronounced activity against both soluble aggregates and plaques in trials [1] [5] [6]. Donanemab is designed to bind an N‑terminally modified, pyroglutamate form of plaque Aβ (N3pG), making it relatively plaque‑selective and aimed at removing established deposits [5] [7]. Aducanumab binds aggregated Aβ and was developed against deposited plaques (amino acids 3–7), producing plaque reduction but with less selectivity for small oligomers/protofibrils compared with lecanemab [1] [4]. These binding preferences matter because protofibrils/oligomers are hypothesized to be neurotoxic and plaque removal may differentially mobilize perivascular amyloid, which is implicated in ARIA risk [1] [2].
2. Efficacy — biomarker clearance versus clinical benefit
All three antibodies produced robust biomarker effects—substantial amyloid lowering on PET and changes in CSF/biomarkers—yet clinical cognitive benefits were consistently small at the group level: lecanemab reduced CDR‑SB by about 27% in CLARITY‑AD, donanemab showed a 35% delay in decline on iADRS in certain tau‑stratified groups, and aducanumab’s clinical efficacy has been disputed despite plaque lowering [2] [7] [3] [4]. Network meta‑analyses conclude that the three agents achieve substantial biomarker responses but only small cognitive effects and that differences in cognitive outcomes across drugs are modest and sometimes sensitive to analytic choices and subgroups [3] [8]. Independent reviewers note that group‑level trial differences are small relative to established symptomatic drugs and that individual meaningful benefit remains uncertain [4] [9].
3. Safety — ARIA and other risks, and how they compare
ARIA (edema/ARIA‑E and microhemorrhage/ARIA‑H) is the dominant safety signal across these antibodies; pooled analyses report higher ARIA rates for lecanemab and donanemab (ARIA‑E rates in the teens percent) and historically higher ARIA incidence reported with aducanumab in some trials [2] [7] [10]. Real‑world pharmacovigilance highlights concerns that removing Aβ may alter immune defenses and be associated with infections or other adverse events, prompting continued monitoring [11] [12]. Rates vary by dose, ApoE ε4 carrier status, and trial timing; ARIA events are often early in treatment and frequently resolve, but serious cases including edema and hemorrhage have been reported, and head‑to‑head safety comparisons remain limited [2] [9].
4. Interpreting differences — what the evidence supports and where it doesn’t
Comparative ranking exercises and NMAs sometimes place donanemab ahead on specific cognitive measures (especially in high‑tau subgroups) and lecanemab ahead on some biomarker endpoints, but results are heterogeneous and sensitive to subgroup definitions, pandemic‑era trial disruptions, and varying endpoints across trials [3] [5]. Long‑term outcome superiority, effects on daily function meaningful to patients, and comparative safety in broad clinical populations are not yet established; some meta‑analyses even find no clear cognitive superiority among the three when all evidence is pooled [8] [13]. The literature thus supports modest disease‑modifying signals tied to mechanism and dosing but stops short of definitive comparative claims.
5. Practical implications and unresolved questions
Clinicians and regulators have moved cautiously: lecanemab achieved conventional approval after CLARITY‑AD evidence while donanemab and aducanumab’s places differ by regulatory status and controversy, reflecting uncertainty about clinical meaningfulness versus biomarker success and ARIA risk [10] [7]. Remaining questions—whether protofibril targeting yields superior long‑term cognitive preservation, how best to manage ARIA across genotypes, and who derives clinically meaningful benefit—require longer follow‑up, head‑to‑head trials, and broader real‑world safety surveillance, areas the current literature emphasizes but does not yet resolve [3] [12] [4].