A new Cochrane review published today has suggested that drugs that target amyloid beta proteins in the brain likely have no clinically meaningful positive effects. 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.
The study compared the effects of seven different therapies: aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, and solanezumab, analysing their effects on cognitive decline and dementia symptoms. The authors concluded that the treatments make little or no difference to people's symptoms and disease progression. However, experts have challenged the findings and the decision to conflate failed drugs with more recent drugs (lecanemab and donanemab) which have been shown to have clinical benefit.
UK DRI researchers respond to the news here:
Prof Bart De Strooper, Group Leader at the UK DRI at UCL, said:
“This review does not clarify the evidence, it blurs it. By mixing failed drugs with the only antibodies that have actually changed clinical practice, it turns therapeutic progress into statistical noise. The flaw in this review is fundamental. In the review itself, the authors acknowledge that while several first-generation antibodies failed, newer antibodies have produced positive clinical effects, yet they still pool them together and treat the resulting average as if it were an informative judgment on the entire field. That inevitably dilutes the signal from the only agents that have successfully changed clinical practice.
“For journalists and non-specialists, the key point is simple. Anti-amyloid antibodies are not one uniform group of medicines. They are different molecules, developed at different times, directed against different forms of amyloid, and associated with very different trial outcomes. Some of the earlier antibodies failed to show meaningful clinical benefit. More recent agents, most notably lecanemab and donanemab, did show measurable slowing of decline in large trials and have therefore changed the therapeutic landscape.
“That is why this review is problematic: once failed and successful programmes are combined into a single pooled estimate, the average will inevitably look weaker than the best performing agents. That is not a biological insight, it is simply the arithmetic consequence of mixing negative and positive studies together. The authors then present that blurred average as though it were a meaningful verdict on anti-amyloid therapy as a whole.
“My concern is not that the review asks a difficult question, it is that it answers in a way that erases the distinctions that matter most. The public is left with the impression that anti-amyloid therapy has broadly failed and that the field should move on. Comparatively, what the literature shows is that many early programmes failed, but that newer antibodies have delivered modest yet real clinical benefit, alongside important safety, cost, and implementation challenges. A serious review should help readers understand that complexity. This one risks obscuring it.”
Prof Sir John Hardy, Group Leader at the UK DRI at UCL, said:
“This paper compares the effects of seven different amyloid beta targeting monoclonal antibodies. The issue is that it conflates different therapies with different mechanisms: for example, aducanumab works by removing existing plaques from the brain, whereas lecanemab primarily binds to soluble forms of amyloid to prevent plaques from forming in the first place. I would refer the readers to the short review by Cath Mummery and I which show that successful therapies follow the disease and treatment modelling predictions proposed by Karran and De Strooper.Successful therapies remove amyloid from the brain, and unsuccessful ones do not."
Prof Paresh Malhotra, Group Leader at the UK DRI Centre for Care Research & Technology and Head of Division of Neurology, Imperial College London, said:
“Several amyloid-targeting antibody treatments for Alzheimer’s Disease have been tested in individual trials over recent years. In the UK and elsewhere, this has resulted in the licensing of two drugs - lecanemab and donanemab- after well-conducted trials showed that they had an effect on multiple measures ofcognition and the ability to carry out everyday activities. They have not been approved by NICE and there has been extensive discussion regarding the side effect profiles of the drugs as well as the meaningfulness of their clinical effects. At the moment there is ongoing work evaluating these drugs as well as other agents that target amyloid plaques.
“The authors of this review have pooled multiple studies that evaluate different drugs with different specific amyloid targets, and their analysis shows ‘small-to-absent’ effects. This is not surprising given that most of these trials have negative effects, but does not take into account the key differences between individual drugs and the trials assessing them. There are many questions that still need to be answered about the licensed drugs including methods and duration of administration. I agree with the authors that other mechanisms of action beyond targetting amyloid for treatment of Alzheimer’s should be explored. However, the findings to-date do not justify ’throwing the baby out with the bathwater’ and dismissing all the results of well-conducted individual studies. The results of ongoing amyloid-targeting trials will help us understand these treatments better, and we should continue to explore all promising avenues for the treatment of Alzheimer’s and other dementia-causing diseases.”
Prof Paul Morgan, Director of the UK DRI at Cardiff University, said:
“This systematic review explored the benefits and harms of anti-amyloid mAbs in patients with MCI or early AD by reviewing data from publications and clinical trials databases. After exclusion criteria were applied, 17 informative studies including ~20,000 patients were included; notably, these involved seven different anti-amyloid mAbs, all compared with placebo.
“The overall conclusion was that treatment with anti-amyloid mAbs, while highly effective at clearing amyloid, had minimal impact on cognition, dementia severity or functional capacity, while increasing the incidence of ARIA with its concomitant risks to health. An issue highlighted in the report was the inconsistency in selection of tests applied to measure cognition and disease severity. The authors conclude that anti-amyloid mAb therapies have minimal impact on key outcomes in patients with MCI or early AD and carry significant risks, highlighting the need to seek alternative approaches beyond the current focus on amyloid removal.
“The findings, while not unexpected by many observers in the field, will likely generate vigorous debate in what has become a key controversy. They support the growing view that removal of amyloid is not, alone, sufficient to significantly improve cognition or slow disease progression when administered early in the disease course. There is an urgent need to understand the drivers of continued disease progression after successful amyloid clearance to identify complementary targets for therapy.
“One could speculate that targeting existing amyloid pathology and efficiently removing plaques is “shutting the stable door after the horse has bolted”. Earlier interventions with anti-amyloid mAbs to prevent plaques from forming in the first place might deliver more impact on the disease, although this requires ways of identifying those at risk before the appearance of overt pathology. Evolving genetic and biomarker tests may soon provide this capacity, although the costs and benefits of population screening are unknown.”
Prof Jonathan Schott, Professor of Neurology and Group Leader at the UK DRI at UCL, said:
“It is clearly important to distinguish between statistical significance and clinical meaningfulness when considering the effect of any drug. However, I question the rationale of jointly analysing trials of multiple different amyloid targeting therapies only two of which (i) have been shown to have robust statistical benefits compared to placebo and (ii) are licensed for clinical use anywhere in the world. By combining studies of different drugs, many of which have long since been disbanded, several of which had little or no effects on beta-amyloid, and most of which have failed in randomised clinical trials, it is almost inevitable that the conclusion will be that as a group they are clinically ineffective. Importantly, however, this does preclude individual drugs from having clinically meaningful benefits.”
Prof Tara Spires-Jones, Professor of Neurodegeneration at the University of Edinburgh, UK DRI Division Lead, and Past President of the British Neuroscience Association said:
“This review by Nonino and colleagues examined data from randomized control trials of antibodies to amyloid beta, one of the proteins that clumps in the brains of people with Alzheimer’s disease. While reviewing clinical trial data is useful, the authors of this study combined analyses of 5 drugs that did not succeed in their trials and 2 drugs that did succeed in slowing disease progression and have been approved to treat early Alzheimer’s disease in several countries. The authors’ conclusion that anti-amyloid antibodies do not provide clinically meaningful benefits is weakened by including 5 drugs that did not pass their clinical trials and are not available. Emerging data on long-term use of the approved drugs and careful analyses by regulators including the European Medicines Agency and UK Medicines and Healthcare products Regulatory Agency (MHRA) support the use of two amyloid antibodies, lecanemab and donanemab, to slow decline in early Alzheimer’s disease. As the authors of this study point out and as was previously published in the original trials, these drugs are not perfect, they come with risks of serious side effects and only modestly slow progression. Due to the limited benefit and high costs accompanied by risks of brain bleeding and swelling, these drugs are not covered by the NHS. However, newer research into both more advanced amyloid targeting drugs and other targets shows promise for improved treatments on the horizon.”
Declared interests:
- Prof Bart De Strooper: I have been consultant and advisor for many pharmaceutical companies, including EISAI, Eli Lilly, Johnson & Johnson, and I have been founder of two spin off companies (Augustine TX and Muna TX).
- Prof Sir John Hardy: John has consulted for Eisai, Lilly and Boehringer Ingleheim.
- Prof Paresh Malhotra: National Specialty Lead for Dementia and Neurodegeneration, NIHR Research Delivery Network
Honorary Consultant Neurologist, Imperial College Healthcare NHS Trust
Group Leader, UK Dementia Research Institute
Serviced Practice Consultant Neurologist, Cleveland Clinic London
NHSE Working Group Member (Lecanemab and Amyloid PET)
Task and Finish Group, Modern Service Framework for Frailty and Dementia
Trustee, Alzheimer’s Society
Clinical Committee, ARUK
Recipient of ‘Drugs Only’ Grant for NIHR funded Trial, Shire/Takeda
Independent Data Monitoring Committee, J&J
Research funding from NIHR, ARUK, Alzheimer’s Society, MRC, DPUK, BHF, Lifearc, FIFA, FA, UK DRI - Prof B. Paul Morgan: No conflicts.
- Prof Jonathan Schott: Jonathan Schott reports providing consultancy or serving on advisory boards for Roche, Eli Lilly, Receptive Bio, Eisai and Biogen and is Chief Medical Officer for Alzheimer’s Research UK.
- Prof Tara Spires-Jones: I have no conflicts with this study but have received payments for consulting, grant reviews, scientific talks, or collaborative research over the past 10 years from AbbVie, Sanofi, Merck, Scottish Brain Sciences, Jay Therapeutics, Cognition Therapeutics, Ono, Novo Nordisk, Eisai, and Boehringer Ingelheim, and direct a company Spires-Jones Neuroscience, Ltd to act as a consultant. I am also Charity trustee for the British Neuroscience Association and the Guarantors of Brain and serve as scientific advisor to several charities and non-profit institutions.
Reference: Nonino F, Minozzi S, Sambati L, Del Giovane C, Baldin E, Bassi MC, De Santis C, Gonzalez-Lorenzo M, Vignatelli L, Filippini G, Richard E. Amyloid‐beta‐targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Cochrane Database of Systematic Reviews 2026, Issue 4. Art. No.: CD016297. DOI: 10.1002/14651858.CD016297.