select search filters
briefings
roundups & rapid reactions
Fiona fox's blog
A systematic review published in the Cochrane Database of Systematic Reviews looks at the use of anti-amyloid monoclonal antibodies for Alzheimer’s Disease.
Prof Ian Maidment, Professor in Clinical Pharmacy, Aston University, said:
“Alzheimer’s is a devastating disease and we desperately need more effective treatments. Drugs, called anti-amyloid drugs, which reduce the build-up of amyloid seen in Alzheimer’s disease have been suggested as effective treatments. They are administered as an infusion usually every two or four weeks.
“This research used “gold standard” methods and summarized all the evidence from the key clinical trials. The review included 17 studies involving 20,342 participants and focused on cognitive function and the severity of dementia after 18 months of treatment. Six studies are currently ongoing, which were not included in the review. One limitation of the included 17 studies was that they contained few people from Black or Hispanic/Latino ethnic groups limiting generalisability.
“The team concluded that while the drugs may show a statistical effect on key symptoms of dementia, this effect was unlikely to be clinically relevant for patients. The research also identified key risks particularly bleeding and swelling in the brain, although the risk was small.
“This issue is currently particularly topical. Originally NICE did not approve the use of two of the anti-amyloid treatments, namely lecanemab and donanemab, on the NHS. Last month NICE announced that they will reassess this original decision. This reassessment will be conducted under the new cost effectiveness thresholds agreed following the USA-UK trade deal last year.
“We don’t yet know the likely cost of these drugs for the NHS. The price for donanemab, in the USA, has been estimated at around $32,000 per year (approximately £24,000 per year). There are also likely to be additional costs associated with monitoring for side-effects and administration; 18 months of Donanemab from private providers including the care package is quoted at £87,507.
“In summary, whilst there is a clear need for effective treatment for Alzheimer’s disease, anti-amyloid drugs may not represent the solution.”
Prof Sir John Hardy, Group Leader at the UK Dementia Research Institute 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.”
References:
Hardy J, Mummery C. An anti-amyloid therapy works for Alzheimer’s disease: why has it taken so long and what is next? Brain. 2023 Apr 19;146(4):1240-1242. doi: 10.1093/brain/awad049. PMID: 36797987; PMCID: PMC10115350.
Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022 Apr;21(4):306-318. doi: 10.1038/s41573-022-00391-w. Epub 2022 Feb 17. PMID: 35177833.
Prof Robert Howard, Professor of Old Age Psychiatry, UCL, said:
“This is a well-conducted review examining the overall effects of 18 months of treatment with seven different amyloid-targeting antibodies in patients with mild cognitive impairment or mild dementia caused by Alzheimer’s disease. The review concludes that treatment made little or no difference to cognitive functioning, dementia severity or functional ability.
“While disappointing, the results and conclusions should not come as a surprise to those who have appreciated the very small benefits of treatment (generally around 2% of the range of changes measured by validated tests of cognitive functioning or functional ability) seen in the individual clinical trials of these drugs. While these benefits may have achieved statistical significance within clinical trials where very large numbers of participants allowed the detection of tiny differences, they did not achieve accepted levels of clinical efficacy or what would be appreciable in an individual patient.
“It’s unfortunate and unfair to people with dementia and their families that some commentators and organisations – internationally and in the UK – have presented the effects and benefits of these treatments in an over-optimistic manner, not supported by robust science and that will have raised false hopes in people affected by dementia. This Cochrane Review should be seen as a potential corrective to some of the misinformation that has come to surround what can be realistically expected from these drugs.
“The review only looked at data from 18 months of treatment with these drugs compared to placebo. Some have argued that longer treatment periods of treatment and follow-up would reveal benefits that increased with the passage of time – as you would anticipate from a treatment that successfully modified the progressive course of Alzheimer’s disease. Unfortunately, the emerging trial data from extended treatment with donanemab and lecanemab that has allowed comparison between those patients who started treatment in the trials 18 months earlier with those who began with placebo, suggests that after three years there is no difference between early and delayed-start participants. This suggests that the drugs do not modify disease course and appear much more likely to be acting as a symptom-improving treatment, in much the same way as seen with the earlier “symptomatic” treatments that we have had for nearly 30 years.”
Prof Paresh Malhotra, 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 B. Paul Morgan, Director, UK DRI Cardiff, 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 Dag Aarsland, Director of the Centre for Healthy Brain Ageing at King’s College London, said:
“The conclusions of this review are based on a meta-analysis of 17 randomized controlled trials involving more than 20,000 participants. This represents a substantial body of evidence, and the authors should be commended for undertaking such an extensive and important analysis. The overall findings are, however, disappointing.
“That said, there are reasons to interpret the results with caution. The included studies are heterogeneous in both design and outcome measures. Most importantly, the decision to pool all seven drugs into a single class-level analysis is open to question. While all of these therapies aim to reduce amyloid, they do so through different mechanisms and target different epitopes. These differences may be clinically meaningful, both in terms of effectiveness and safety.
“It is also notable that, among the 17 trials, only two evaluated the drugs that have more recently been approved by European regulators on the basis of what was considered an acceptable balance between benefit and risk. In my view, the conclusions supporting those individual approvals remain valid, despite the findings of this pooled, class-level meta-analysis.”
Prof Andrew Doig, Professor of Biochemistry, University of Manchester, said:
“There has been much excitement in recent years over antibodies that bind to various forms of amyloid-b, as therapies against Alzheimer’s Disease (AD), with claims that some can slow down the loss of cognition that is typical of AD.
“This is a comprehensive and careful study of the effects of these antibodies in clinical trials, focussing on effects on cognitive symptoms and possible harmful effects from brain swelling and bleeding. Only the most reliable trials are considered, leaving seven antibodies studied in 17 separate trials. Overall, the results are a big disappointment. While a beneficial effect on brain function is just about detectable when the results are pooled, the effect is so small that it would never be noticed in practice. In addition, the risk of brain swelling from the drugs is real, even though only a small fraction of patients is affected. The drugs can remove amyloid-b from the brain, as they were designed to do, but this does not translate into benefitting brain function or reducing dementia.
“The authors claim that the entire strategy of targeting amyloid-b is invalidated by their results, particularly as a few studies that remove amyloid-b before any symptoms were apparent are also unsuccessful. I still think that it is premature to be that pessimistic.Targetting subsets of people who have a genetic predisposition to AD, or who show AD biomarkers in the blood may still work, though we cannot expect a large effect. In any case, other strategies against AD must be vigorously pursued.”
Prof Bart De Strooper, Group Leader at the UK Dementia Research Institute 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 Tara Spires-Jones, Professor of Neurodegeneration at the University of Edinburgh, Division Lead in the UK Dementia Research Institute, 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.”
Prof Jonathan Schott, Professor of Neurology and Group Leader, UK Dementia Research Institute, 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.”
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.
“It’s essential that we interpret this review with nuance and avoid taking a sledgehammer to decades of pioneering scientific study.
“Alzheimer’s 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.”
Dr Susan Kohlhaas, Executive Director of Research at Alzheimer’s Research UK, says:
“This review attempts to assess the impact of anti-amyloid drugs for Alzheimer’s, but it has major limitations for people affected by the disease. Much of the evidence it relies on comes from older experimental drugs that were discontinued from development due to failed trials.
“Crucially, this study is attempting to paint an entire class of drugs with the same brush even though we know different anti-amyloid treatments can act in different ways.
“Only two of the 17 studies included were for the medicines now approved in the UK, lecanemab and donanemab. The rest focused on drugs that were not pursued after failing to show meaningful benefit, inevitably shaping the review’s conclusions.
“Although the review highlights the known risk of ARIA on brain scans, the studies it looked at don’t consistently report how often this led to symptoms or how those symptoms were managed. The review itself doesn’t fill an important gap in our understanding of how safe these drugs are in a healthcare setting.
“The review also suggests these treatments are not ‘clinically meaningful’. But there is no agreed definition on what that means and current trial measures don’t always reflect what matters most to people with dementia. We regularly hear from families affected by dementia that even a delay of several months in decline could provide valuable, meaningful time with loved ones and that shouldn’t be minimised.
“Newer, longer-term evidence suggests that the approved treatments may deliver modest but sustained benefits beyond the 18-month horizons of earlier studies, yet this emerging data is not reflected in the review.
“That is why Alzheimer’s Research UK is clear that longer‑term evidence from routine healthcare settings is needed, to understand how these treatments should be used in practice. Initiatives like ACCESS AD will be crucial to further our understanding, as this is designed to show how these medicines perform when offered through standard NHS pathways.
“Anti-amyloid treatments will not be the whole answer to curing Alzheimer’s, and research is already moving towards a wider range of biological targets. But it’s not accurate to dismiss their impact as ‘trivial’, especially when the analysis has clear constraints that limit what it can tell us.”
From our friends at the All-Ireland SMC:
Dr Andrea Kwakowsky, Associate Professor in Pharmacology and Therapeutics, University of Galway, said:
“While the outcomes of recent trials and this systematic review are disappointing, more work is needed to fully understand the potential of these therapies.
“Of all anti-amyloid drugs, only two, lecanemab and donanemab, have been approved and are currently marketed, showing modest cognitive and functional improvements. A major review by Nonino and colleagues found these benefits fall short of what doctors consider clinically meaningful.
“Importantly, many of the drugs discussed in that review were never approved, while these two approved and most promising options are still under active evaluation in ongoing trials to better understand their efficacy and safety.
“This distinction is crucial. The authors’ press release makes some very strong claims, but despite the modest results to date, there is still cautious optimism that these therapies could be more effective in specific subgroups of patients. Taking the APOE4 genotype into account might be a game-changer.
“An Alzheimer’s disease risk gene APO ε4, is a major contributor to and modifier of disease trajectory, therapeutic responses, brain swelling and bleeding, which are the main risks of anti-amyloid therapies. While the authors considered a subgroup analysis stratified by APOE ε4 status, they were unable to do so because testing for this gene is not part of usual clinical practice. By integrating genetic testing into trial design and treatment planning and adopting an early-disease-stage-specific individualised approach, a safer, more effective treatment may be achieved.
“As future research moves forward, several shifts are occurring in the field. The therapeutic targets are being reevaluated, and new targets are being examined, which include neuroinflammation, vascular dysfunction, endocrine dysregulation (including insulin resistance), and lipid metabolism (with a focus on the APOε4 gene). The key to success is a better understanding of the underlying biology of Alzheimer’s disease, which could lead to a more systematic approach to the disease rather than focusing on the better-established targets such as amyloid.”
‘Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease’ was published in the Cochrane Database of Systematic Reviews at 01:00 UK time on Thursday 16th April.
Declared interests
Prof Ian Maidment: No conflicts of interest.
Prof Sir John Hardy: John has consulted for Eisai and Lilly
Prof Robert Howard: Unpaid consultancy for Synaptogenix in 2023.
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 Dag Aarsland: I have been paid consultant to several of the drug companies with relevant drugs, including Eisai, BioArctic and Eli Lilly.
Prof Andrew Doig: He is a founder and director of PharmaKure, a spin-out company working on diagnostics and drugs for Alzheimer’s Disease and other neurodegenerative conditions.
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 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.
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.
Dr Richard Oakley: No interests to declare.
Dr Susan Kohlhaas: “Dr Kohlhaas has no declarations of interest.”
Dr Andrea Kwakowsky: “No interests”
This Roundup was accompanied by an SMC Briefing.