Antibody treatments that target amyloid plaques in the brains of people with Alzheimer's have shown promise in trials, but questions about their side effects and practicality remain.
Judging by some recent newspaper headlines, the prospects of an effective treatment for Alzheimer’s disease have never been better. In the past couple of years, positive trial results have been announced for three drugs that clear a protein called amyloid – which is thought to play a crucial role in this form of dementia – from the brain.
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| Illustration of amyloid plaques in a brain affected by Alzheimer’s disease NOBEASTSOFIERCE/SCIENCE PHOTO LIBRARY |
But not everyone is convinced. Sceptics point out that these treatments won’t have much impact on symptoms. They can also cause dangerous brain bleeds or swelling and aren’t practical for widespread use. So, are the amyloid-busting drugs worth getting excited about or are they just a mirage?
Certainly, some kind of breakthrough is sorely needed against Alzheimer’s, the most common form of dementia. Due to rising life expectancies, Alzheimer’s is on the increase and current drugs only slightly alleviate the symptoms of memory loss and confusion, without doing anything to slow the condition’s progress.
A build-up of amyloid in the brain has been suspected as the root cause of Alzheimer’s since the 1980s. Clumps of this protein, known as plaques, can be seen in the brains of those affected and the few genes that have a strong causative role in early-onset Alzheimer’s raise amyloid levels.
But the quest to develop amyloid-destroying drugs hasn’t gone smoothly. After dozens of compounds designed to lower amyloid one way or another failed in trials, doubts were raised about whether the amyloid hypothesis of Alzheimer’s was even correct.
More recently, the amyloid story turned a corner. In 2021, a drug called aducanumab – which consists of antibodies that bind to amyloid – was approved by the US Food and Drug Administration (FDA) on the basis that it reduces amyloid plaques, despite having no effect on memory.
In January 2023, the FDA approved a second amyloid antibody called lecanemab, which both reduces plaques and, crucially, slows memory decline. Then, this month, results showing a similar slowing of memory loss were released for a third antibody called donanemab.
Each of these events was welcomed by patient support groups, with some media reports describing the treatments as a “momentous breakthrough”. “In the space of six months, we have had two disease-modifying treatments that not only show the removal of amyloid, but also show patient benefit,” says Richard Oakley at the UK’s Alzheimer’s Society. “We are in a new era.”
But look a little closer and the picture may not be so rosy. Firstly, it is doubtful if any of the drugs have an effect on memory that is big enough to be noticeable by people with Alzheimer’s or their families. For instance, in the 18-month trial of lecanemab, those receiving the drug worsened by 1.2 points on an 18-point scale used to rate dementia symptoms. Those who got a placebo worsened by 1.7 points – just half a point more. Doctors have previously estimated that it would take a minimum of a 1-point difference on this scale for a treatment to make a meaningful improvement to people’s lives. A 0.5-point difference is really undetectable, says Lon Schneider at the University of Southern California, Los Angeles.
While the antibodies have been lauded as the first “disease modifying” treatments, the size of their effects on this 18-point scale is about half that seen with the available drugs that just mitigate symptoms, says Rob Howard at University College London.
A spokesperson for lecanemab’s manufacturer, Eisai, says: “We are confident that the results demonstrated by the study are clinically meaningful. For patients in the early Alzheimer’s stage, a change of score [of half a point] in the memory domain means progressing from benign forgetfulness to moderate memory loss.” Donanemab’s manufacturer, Lilly, says the paper that suggests a 1-point change on the symptom scale is needed was referencing differences between individuals, not the averaged effects on groups of people. “Application of such differences to a treatment group versus an individual patient level may be misleading.”
Nevertheless, another concern is side effects. The antibodies seem to bind to amyloid within the walls of blood vessels in the brain. This can lead to leakage of fluid from the blood vessels, resulting in brain swelling, bleeding and, in a few cases, deaths. “Having a kind of immune reaction to something in the wall of your blood vessel isn’t great for that blood vessel’s integrity,” says Howard.
Yet this alone doesn’t have to be a dealbreaker for the drugs’ use, says Dennis Selkoe at Harvard Medical School. Other drugs have risky side effects, such as those for treating cancer or multiple sclerosis, but we inform people about these adverse events and let them decide. People can also take genetic tests to see if they are at a higher risk of both Alzheimer’s and these side effects, although that can cause its own issues.
Setting aside concerns over safety and efficacy, the treatments also bring practical difficulties. The antibodies have to be given by regular infusions and recipients need regular brain scans to check for brain swelling or bleeding.
Even in the US, most health insurers won’t cover the cost of the two treatments approved so far. For lecanemab, the leading contender in this field, this will probably be $26,500 a year because it hasn’t yet gained the standard form of FDA approval, only the more tentative “accelerated approval”.
The final FDA decision on lecanemab is due in July. Until then, Medicaid and Medicare – the country’s two biggest public health insurers – will only fund its use as part of research. One public insurer, the Veterans Health Administration, has agreed to fund lecanemab for general use, but most private insurers follow the lead of Medicaid and Medicare.
In the UK, where new medical treatments can only be introduced if they are judged to provide value for money by bodies such as the National Institute for Health and Care Excellence (NICE), prospects for these drugs’ use seem more remote. It doesn’t help that they wouldn’t slot neatly into current healthcare for people with dementia. The drugs are designed to be given early in the condition’s onset and, at the moment, people with dementia symptoms may not get a formal diagnosis until relatively late in their illness, if at all. Care is also generally provided by mental health services that lack brain-scanning machines or the ability to give antibody infusions.
On the other hand, if the antibodies were to trigger an overhaul of dementia care, meaning more people get an early diagnosis, that could bring its own benefits, says Oakley. But given the treatments’ barely detectable effects on memory, such arguments seem unlikely to sway NICE, says Howard.
All these issues are leaving people affected by Alzheimer’s and their families in a kind of limbo. There are news reports of breakthrough treatments, yet, in practice, the drugs aren’t available. People may read claims that the drugs are disease modifying, but, in reality, they will probably have no noticeable effects.
Howard says the amyloid antibodies should be seen as somewhat of an advance for Alzheimer’s science, by confirming that the protein plays a role in the condition. “This is positive news, but it is a tiny, incremental step that probably isn’t going to have a big impact in the clinic,” he says. “In 10 years’ time, I’ll be very surprised if lots of patients are on these drugs.”
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