When reviewing studies of Alzheimer’s treatments that have already largely failed, the conclusion that they are clinically ineffective is, experts warn, a foregone conclusion. This inherent bias in analysis is now at the heart of a major debate over the value of a new generation of licensed drugs.
The controversy stems from a recent wide-ranging Cochrane review, which assessed data from 17 clinical trials involving over 20,000 people. It concluded that anti-amyloid drugs showed only “trivial” effects on cognition and dementia severity over 18 months. The authors stated there was a “convincing body of evidence” pointing to “no clinically meaningful effect.” However, the methodology has drawn sharp criticism for combining disparate studies.
Why combined studies skew results
The core of the issue, according to leading neurologists, is that such reviews aggregate data from drugs with vastly different profiles. This includes treatments long since abandoned, others that had minimal impact on the brain’s beta-amyloid protein—a key target—and most which have already failed in definitive randomised clinical trials.
Professor Jonathan Schott, a professor of neurology at UCL and Chief Medical Officer for Alzheimer’s Research UK, explains the inevitable outcome of this approach. “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,” he said.
Other experts, such as Professor Charles Marshall, concur, arguing that pooling results from effective and ineffective treatments would naturally produce a small or absent average treatment effect. Alzheimer’s Research UK has also raised concerns that the review’s methodology may not fully reflect patient and family experiences.
Licensed drugs caught in the crossfire
This academic debate has direct consequences for two recently licensed medicines: lecanemab (Leqembi) and donanemab (Kisunla). Both are anti-amyloid drugs designed to remove beta-amyloid plaques from the brain in early-stage Alzheimer’s. The Medicines and Healthcare products Regulatory Agency (MHRA) has approved them for use in the UK, with lecanemab being the first such treatment licensed in Great Britain in over two decades.
Despite this, neither drug has been recommended for use on the NHS by the National Institute for Health and Care Excellence (NICE). The watchdog has concluded that the benefits—slowing disease progression by approximately four to six months—are too small to justify their high cost and the substantial resources needed for administration and monitoring through regular brain scans. For instance, cost-effectiveness estimates for donanemab were significantly above NICE’s acceptable threshold.
NICE is currently revisiting its decision after an appeal argued it failed to adequately consider the wider impact on unpaid carers. The economic context is stark, with the cost of informal dementia care in the UK alone estimated at over £20 billion annually.
Proponents argue that even a delay of several months can be valuable for families. Some leading figures, including Professor Sir John Hardy, acknowledge the drugs are imperfect but believe they “have opened the door to a new era of treatment” by proving that slowing Alzheimer’s is possible.
Beyond amyloid: new targets and diagnostics
While the amyloid debate continues, research is expanding into other areas. Scientists are exploring treatments that target tau protein, which forms toxic tangles inside neurons. There is also interest in repurposing GLP-1 drugs, used for diabetes and obesity, though recent trial results have been mixed; semaglutide failed to slow Alzheimer’s progression, while liraglutide showed promise.
Parallel progress is being made in diagnosis. Significant work is underway to develop blood tests for early Alzheimer’s detection, with the aim of integrating them into the NHS by 2029. Professor Schott, whose research interests include early diagnosis and pre-symptomatic detection, is involved in studies exploring the utility of these blood-based biomarkers.