Drugs that target amyloid plaques to treat Alzeimer’s disease have no clinically meaningful effect, according to a new Cochrane review.

The review examined data from 17 clinical trials with over 20,000 participants, all looking at the impact of anti-amyloid drugs on people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. They say that while early trials showed results that were promising, further analysis showed this did not translate into a clinically meaningful benefit for patients, while increasing the risk of bleeding and swelling in the brain.

The All Ireland SMC asked local experts to comment. Our colleagues at Science Media Centres in Australia, Spain, the UK and Korea have also gathered comments.

Dr Andrea Kwakowsky, Associate Professor in Pharmacology and Therapeutics, University of Galway, comments:

“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.”

  • What are the implications for health system decision-making, access and funding in Ireland?  

“As it stands, there are major barriers to effective treatment utilising anti-amyloid drugs: limited benefits, high costs, restricted access, and strict eligibility rules. While lecanemab and donanemab are EU-approved, these therapies are not yet available through the HSE in Ireland, but are currently under review by the Health Products Regulatory Authority (HPRA).

“The Irish health system will require a major infrastructure upgrade and guidelines in place to allow people with Alzheimer’s disease to access these therapies – with clearer guidelines, earlier and more accurate diagnosis, and robust monitoring to ensure patient safety.”

Declaration of interests: Professor Kwakowsky declares no conflicts of interest