Research

Alzheimer's Society and leading experts respond to claims anti-amyloid drugs are ineffective

Last week’s report by the Cochrane Collaboration, which concluded breakthrough Alzheimer’s drugs are unlikely to benefit people living with the disease, has attracted widespread debate and some criticism from many in the dementia research community.

As dementia is the UK’s biggest killer and hope around this devastating condition is fragile, Alzheimer’s Society has a responsibility to support those affected to navigate this complex issue. It is essential we challenge whether some of the conclusions reached in this report are an accurate representation of amyloid targeting therapies for Alzheimer’s disease today.

Amyloid is one of the key proteins involved in Alzheimer’s disease, where it clumps together forming plaques. As these plaques build, it causes brain cells to die, and this leads to the symptoms we know as dementia. Anti-amyloid therapies, which are the focus of the report, aim to recognise amyloid in the brain, and work with the brain’s immune cells to clear it.

The problem of pooled data

It is perhaps unsurprising when analysing data pooled from 17 clinical trials, of which 15 were unsuccessful or discontinued, that the overall picture seems bleak.

Dr Ross Dunne, University of Manchester, said, 'While all these antibodies were engineered to reduce amyloid, we know now that not all of them could. Some of them are no more use in Alzheimer's than they would be in rheumatoid arthritis. Comparing older with more modern drugs in a rapidly developing field is bad science.'

Lumping old and unsuccessful drug trials in with newer, more promising ones does not take into consideration the important differences between them. This includes the seven different drugs being assessed, the participants involved and how each drug works to target amyloid plaques (for example lecanemab targets amyloid before plaques have formed and donanemab targets plaques once formed).  

Dr Dunne continues, 'Five of the seventeen trials in the Cochrane review did not require participants to have biomarker-confirmed Alzheimer's disease at entry, and follow-up studies showed that roughly a quarter of those participants did not have the disease at all.'

In hindsight, given the circumstances, it’s unsurprising that a high percentage of these trials did fail.  

A poor reflection of the progress

The authors of the review claim these drugs show no ‘clinically meaningful benefit for patients'. However, we must acknowledge that measuring and defining what can be considered ‘clinically meaningful’ for people living with Alzheimer’s disease is incredibly challenging and highly subjective. The tools used in trials currently available may not always reflect what matters to those affected, a challenge that is acknowledged across the field.  

However, despite the difficulties, it’s critical we do not uniformly label these treatments and trials as failures and throw this hard-won baby out with the bathwater.  

This Cochrane review glosses over important nuances and erases the principle through which research makes progress. We learn what works and what doesn’t through sequential trials, many of which will fail, and use this information to develop the next trial. 

Ultimately, this will lead to new and ever more effective drugs, with side effects that are managed better, more understanding of which patients the drugs will be most effective for and at which point in their dementia journey. This is exactly what has happened in other diseases, such as cancer.  

Professor Vanessa Raymont, University of Oxford said, 'Such vital guidance depends on nuanced interpretation, and it is unacceptable that this review does not reflect the current evidence or meaningfulness for those affected by Alzheimer’s disease.'

For decades there have been failed trials in Alzheimer’s disease and dementia more widely and only in the last five years has the field seen the first treatments successfully slow its progression. We mustn’t let this hope slip away.

We see this progress already with the two most recent anti-amyloid drugs, lecanemab and donanemab, approved by the MHRA as safe and effective and, which are available to people living with Alzheimer’s in other parts of the world.  

What needs to happen next  

We agree with the authors that it’s important to support research into the longer-term impacts of these drugs. And we must also acknowledge the sometimes serious side effects that come with anti-amyloid drugs, which we must continue research to manage and reduce.

Professor Paresh Malhotra, Imperial College and Alzheimer’s Society trustee said, 'I believe that it is important to look at the strengths and flaws of these drugs and to understand how their positive effects might be enhanced and their side effects reduced. Such studies are ongoing, and I think this type of work is more likely to benefit patients than dismissing all of these drugs.'

We also wholeheartedly agree (and it has always been the case that) other avenues need to be explored, amyloid is only one part of a highly complex disease. 

We know anti-amyloid drugs are not a silver bullet. In fact, no single treatment is likely to be sufficient, and future approaches will need to target multiple pathways.  

We do not agree with the authors conclusion that treatments and research targeting amyloid should be abandoned.

Professor Malhotra continues, 'The methodology used in their review was flawed and their main conclusions were too damning of anti-amyloid antibody-based treatments.'

Especially with the next generation of promising late-stage trials underway that continue to build on the lessons learned from the trials that came before.

Professor John O’Brien, University of Cambridge and Alzheimer’s Society Research Strategy Council Chair said, 'While it is true that much more effective treatments for Alzheimer’s disease are needed, there is increasing evidence that drugs that are the fastest and most effective at lowering amyloid levels in the brain are the ones which show clinical benefits.'

Protecting future progress  

But for these future approaches to succeed (whether they be amyloid targeting or targeting another disease process), we need people to take part in clinical trials. It’s already difficult for people living with dementia to access clinical trials in the UK hindering potential breakthroughs we so desperately need in dementia.  

The damage the claims of the Cochrane review could have on clinical trial recruitment cannot be underestimated – Alzheimer's Society has already been contacted by individuals questioning the value of taking part in clinical research as a direct result of the review and the media surrounding it.  

Research will beat dementia and we believe anti-amyloid treatments will form a part of the way we achieve that aim. But there will need to be much more research done to develop other treatments, ultimately leading to people receiving combinations of treatments, personalised to their dementia, just like we see in other diseases. Diagnosing and treating earlier in the course of the disease will be critical.  

The fight to beat the UK’s biggest killer will be long and full of challenges but Alzheimer’s Society will not stop until we have ended the devastation caused by dementia.