A new meta-analysis has found that amyloid-clearing drugs — including lecanemab and donanemab — show no clinically meaningful cognitive benefit and carry an increased risk of complications, including brain swelling and bleeding.
The review, published by Cochrane, pooled data from 17 trials of seven different medicines and found that the drugs' effects on cognition and dementia severity during an 18-month period were "trivial," with improvements in functional ability "small at best."
Elevated levels of amyloid beta protein are a hallmark of Alzheimer's disease. The proteins aggregate into plaques in the brain, which are thought to accelerate cognitive decline.
Amyloid-clearing drugs — a class of monoclonal antibodies — bind to the protein to facilitate its clearance, aiming to slow disease progression rather than merely manage symptoms.
Two such drugs have received regulatory approval in the US to date: Leqembi (lecanemab, manufactured by Eisai), approved in 2023 and Kisunla (donanemab, manufactured by Eli Lilly), approved in 2024. Leqembi, in particular, was widely regarded as a turning point after decades of clinical failures in the Alzheimer's space.
In the UK, both were approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) in 2024, though the National Institute for Health and Care Excellence (NICE) initially declined to recommend them on cost-effectiveness grounds.
"Absent or trivial" results
The Cochrane team pooled data from 20,342 participants across 17 studies. As well as lecanemab and donanemab, the analysis included several first-generation anti-amyloid therapies (aducanumab, bapineuzumab, crenezumab and solanezumab), all of which have since been discontinued following unsuccessful trials or withdrawal by their manufacturers.
Standard cognitive assessments at 18 months showed beneficial effects that "were absent or trivial, falling well below the established thresholds for the minimum clinically important difference," the authors stated.
Lead author Francesco Nonino said: "Unfortunately, the evidence suggests that these drugs make no meaningful difference to patients."
While early trials showed results that were statistically significant, it is important to distinguish between this and clinical relevance.
"It is common for trials to find statistically significant results that do not translate into a meaningful clinical difference for patients."
The review also identified an increased risk of brain swelling and bleeding, though the researchers noted these adverse events were detected on imaging scans and were asymptomatic in most patients. The authors further flagged inconsistent reporting of both efficacy outcomes and adverse events across the included studies.
Industry and clinical pushback
The analysis has drawn significant criticism, primarily for its methodology of pooling approved, newer-generation drugs with older, failed compounds. Critics argue that this obscures meaningful differences in efficacy.
"Bundling these drugs together to make an overall conclusion is odd," said Dr Jason Karlawish, Professor of Medicine, Medical Ethics and Health Policy and Neurology at the University of Pennsylvania's Perelman School of Medicine.
The field is still sorting out what kinds of anti-amyloid molecules and dosages are effective.
Critics also questioned the 18-month assessment window for a slowly progressing disease, with researchers noting that longer-term data suggests sustained benefits for patients who remain on treatment.
Eisai was pointed in its response: "The Cochrane analysis is scientifically deeply flawed by inappropriately combining ineffective antibodies and failed studies with effective, regulatory-approved anti-amyloid treatments."
The company pointed to the FDA's own characterisation of lecanemab as part of "a newer generation of anti-amyloid therapies" that has "learned from previous failures" and cited four years of long-term clinical data alongside real-world use across tens of thousands of patients globally.
UK regulatory implications
The findings land at a sensitive moment for the UK market. NICE is currently reassessing its recommendation on both lecanemab and donanemab following an appeal from manufacturers.
The review will apply new, higher cost-effectiveness thresholds introduced as part of a US trade agreement — a development that could significantly affect whether either drug reaches NHS patients.