Drugs that target amyloid beta proteins in the brain likely have no clinically meaningful positive effects, while increasing the risk of bleeding and swelling in the brain, a new Cochrane review has found.
People with Alzheimer’s disease have high levels of a protein known as amyloid beta in their brains, detectable before symptoms begin, but its role in disease progression is uncertain. Drugs have been developed to remove these proteins from the brain, under the theory that this would prevent or slow disease progression.
The new review examined data from 17 clinical trials with a total of 20,342 participants, all looking at the impact of anti-amyloid drugs on people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Proponents of these drugs have theorised that they would be more effective at these earlier stages before the disease has progressed.
Absolute effects “well below clinical threshold”
The research found that the absolute effects of anti-amyloid drugs on cognitive decline and dementia severity were absent or trivial, falling well below established thresholds for the minimum clinically important difference.
“Unfortunately, the evidence suggests that these drugs make no meaningful difference to patients,” says lead author Francesco Nonino, neurologist and epidemiologist at the IRCCS Institute of Neurological Sciences of Bologna, Italy. “There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect. 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.”
In addition to the absence of clinically meaningful effects, the review found that anti-amyloid drugs likely increase the risk of swelling and bleeding in the brain. This was observed in brain scans without any apparent symptoms for most patients, although any long-term effects remain unclear since reporting of symptoms was inconsistent across trials.
Future research should focus on other pathways
On the basis of the evidence, the authors conclude that future trials targeting amyloid beta removal are unlikely to provide clear benefit to patients. They found that these drugs do successfully remove amyloid proteins from the brain, but this does not translate into meaningful clinical benefit. They recommend that future research on Alzheimer’s treatment should focus on other mechanisms, with numerous studies ongoing in other directions.
“I see Alzheimer’s patients in my clinic every week and I wish I had an effective treatment to offer them,” says senior author Edo Richard, Professor of Neurology at Radboud University Medical Centre. “Existing approved drugs offer some benefit for some patients, but there remains a high unmet need for more effective treatments. Sadly, anti-amyloid drugs do not offer this and bring additional risks. Given the absence of correlation between amyloid removal and clinical benefit, we need to explore other pathways to help address this devastating disease.”
Responding to the research findings, Dr. Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said: "It’s not the case that all amyloid-targeting drugs are ineffective. This review’s conclusions make the picture look bleaker than it really is, as authors combined results for a majority of failed drug trials with a small number of more recent successful trials. This includes the trials for lecanemab and donanemab which the UK medicines regulator agreed bring a modest but meaningful benefit for people with early-stage Alzheimer’s disease.
"It’s essential that we interpret this review with nuance and avoid taking a sledgehammer to decades of pioneering scientific study. Alzheimer’s disease is highly complex and a combination of treatments will likely be needed to target a range of processes involved in its development. Anti-amyloid drugs are just one treatment avenue and not a silver bullet. We consider anti-amyloid drugs still to be a valid avenue to explore and optimise, reducing side effects, understanding their longer term impacts and ultimately bringing us closer to tackling Alzheimer’s for the millions of people affected globally."
View the paper at: Amyloid‐beta‐targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease - Nonino, F - 2026 | Cochrane Library
View the Alzheimer’s Society's full response at: New Cochrane review of amyloid targeting Alzheimer’s disease treatments | Alzheimer's Society
