Alzheimer’s Drugs That Target Amyloid Plaques Have No “Meaningful” Effects, Says Major Review, Sparking Fierce Debate From Scientists

Dementia, the majority of which is caused by Alzheimer’s disease, is projected to affect around a million US adults per year by 2060. This is a rapidly growing public health challenge with few if any treatment options available to most patients by the time they are diagnosed. 

In 2021, a milestone was reached when the US Food and Drug Administration (FDA) approved its first Alzheimer’s drug in 18 years. Called aducanumab, the monoclonal antibody targets the buildup of amyloid-β in the brain – a hallmark of the disease – aiming to clear some of these plaques away.

While there was excitement surrounding the drug, there was also skepticism – it was unclear whether removing the amyloid would actually have a positive effect on patient’s symptoms, and there were also some serious side effects noted in the trials for some individuals, including an increased likelihood of brain bleeds and brain swelling. 

Aducanumab was eventually discontinued by manufacturer Biogen, not for safety or efficacy reasons, but because the company was reconsidering how it should “allocate its resources”. Since 2021, however, a swathe of new anti-amyloid drugs based on a similar premise have reached different stages of development. 

Other notable examples include donanemab – which was found to compare favorably with aducanumab in a pioneering virtual clinical trial as well as producing impressive results in human trials. There’s also lecanemab, similarly hailed as a breakthrough. However, in both cases, the kinds of problems seen with aducanumab remained. The side effects, for instance, could be serious and even fatal. 

When the UK’s National Institute for Health and Care Excellence (NICE) assessed whether lecanemab and donanemab should be made available through the country’s National Health Service, it concluded that they shouldn’t be because they wouldn’t provide value for money.

Both drugs passed safety assessments from the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the US FDA, however, meaning they are available in both countries through private healthcare.

Other drugs with similar mechanisms have failed to produce such promising trial results, leading some to question the validity of the anti-amyloid approach altogether. These sentiments have been compounded by a few notable incidents, including the retraction of a widely cited paper due to doctored images and accusations of conflicts of interest in the committee that approved donanemab.

The new Cochrane review has examined 17 clinical trials of nine anti-amyloid monoclonal antibodies, including the three we’ve mentioned. In total, the analysis comprised data from over 20,000 participants with either mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s. MCI can be a precursor to full-blown dementia, and proponents of these drugs have theorized that they could have maximal benefits when used at this stage.

According to the review, the effect of these drugs on patients with either MCI or dementia is “trivial.” Even if they work as intended and clear amyloid from the brain, the reviewers were not clear that this would translate into an improvement in symptoms:

“Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.”

That sounds pretty damning, but some researchers in the field aren’t wholly surprised.

“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 percent of the range of changes measured by validated tests of cognitive functioning or functional ability) seen in the individual clinical trials of these drugs,” commented Robert Howard at University College London (UCL) to the UK’s Science Media Centre (SMC).

“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.”

The first author of the review, neurologist and epidemiologist Francesco Nonino at the IRCSS Institute of Neurological Sciences of Bologna, Italy, said in a statement: “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.”

However, other researchers have pushed back, raising concerns about how the review reached its conclusions and querying the pooling together of trial results for different generations of drugs that work in different ways.

“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,” Bart De Strooper at the UK Dementia Research Institute and UCL told the SMC.

“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.”

This, De Strooper and others argue, could lead to a premature move away from anti-amyloid therapies just as newer generations of these drugs start to show clinical benefits. 

“It’s not the case that all amyloid-targeting drugs are ineffective,” said Richard Oakley, Associate Director of Research and Innovation at the Alzheimer’s Society in the UK. “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.”

“It’s essential that we interpret this review with nuance and avoid taking a sledgehammer to decades of pioneering scientific study.”

The reviewers note that, as pointed out by some commentators, there are still trials ongoing for these drugs, stating: “The review's conclusions may change as new results become available.”

That said, Cochrane systematic reviews are generally seen as the gold standard of evaluating clinical evidence. Often, the publication of such a review serves to help settle a debate on a topic, not inflame it even more.

Arguments over the anti-amyloid approach to Alzheimer’s treatment are not new to those in the field – and with more and more people being affected by the disease, these arguments remain far from settled.

Robert Howard stated to the SMC that he had done unpaid work for Synaptogenix, a company involved in developing Alzheimer’s drugs. Bart De Strooper said he has founded two companies involved in developing Alzheimer’s drugs.

Robert Howard and Bart De Strooper both declared conflicts of interest to the SMC. For more details click here.

The study is published in the Cochrane Database of Systematic Reviews.