Drugs that have been hailed as a gamechanger for the treatment of Alzheimer’s disease make no noticeable difference to patients, according to an extensive review.
The analysis of clinical trials in people with mild cognitive impairment or mild dementia found that the effects of anti-amyloid drugs on cognition and dementia severity over 18 months were “trivial”, with improvements in functional ability “small at best”.
The verdict is a blow to the new wave of drugs that are designed to slow Alzheimer’s by clearing clumps of amyloid protein that build up in the brain. Amyloid plaques are a hallmark of Alzheimer’s disease, along with another protein called tau which forms toxic tangles in neurons.
The Cochrane review drew on gold standard methods to assess data from published clinical trials, but was criticised by some researchers and charities for combining results from older, failed drugs with those from newer, more effective medicines.
“It’s not surprising that if you pool results from effective and ineffective treatments you end up with a small or absent average treatment effect,” said Charles Marshall, professor of clinical neurology at Queen Mary, University of London.
Anti-amyloid drugs were hailed as a gamechanger when clinical trials showed small but statistically significant improvements in patients. Medical regulators around the world approved lecanemab made by Eisai, and donanemab, made by Eli Lilly, but many countries stopped short of providing them through public health services.
In the UK, the National Institute for Health and Care Excellence (Nice) said that despite the drugs slowing the disease by four to six months, the cost to the NHS was not justified. Nice is revisiting the decision after an appeal by the manufacturers.
The Cochrane review analysed 17 clinical trials that typically lasted 18 months. They involved more than 20,000 people and assessed seven anti-amyloid drugs in people with mild cognitive impairment or dementia.
Edo Richard, a co-author on the review and professor of neurology at Radboud University medical centre in the Netherlands, said the analysis found “no clinically meaningful effect on cognitive decline or dementia severity”, and that the drugs caused more swelling and bleeding in the brain than the placebo.
“These effect sizes are too small for patients and caregivers to notice,” Richard said, adding that the drugs were also “burdensome” because patients must visit a clinic every two to four weeks to receive the intravenous drug infusions and have regular MRI scans to check for brain swelling or bleeding.
He defended the decision to pool results from different drugs as all aimed to remove amyloid from the brain and assessed the impact on patients in a similar way. The review concludes that researchers should explore new ways to treat the disease.
Robert Howard, professor of old age psychiatry at UCL, said emerging trial data for anti-amyloid drugs raised doubts about whether they truly altered the course of Alzheimer’s. “It’s very difficult being the person who says these things, but I don’t think it’s fair on patients to have expectations raised,” he said. “The sad truth is that even the best-performing drugs don’t do anything that’s clinically meaningful.”
Dr Susan Kohlhaas at Alzheimer’s Research UK said: “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.
“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.”
