Judging by some recent newspaper headlines, the prospects of an effective treatment for 础濒锄丑别颈尘别谤鈥檚 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 鈥� which is thought to play a crucial role in this form of dementia 鈥� from the brain.
But not everyone is convinced. Sceptics point out that these treatments won鈥檛 have much impact on symptoms. They can also cause dangerous brain bleeds or swelling and aren鈥檛 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 础濒锄丑别颈尘别谤鈥檚, the most common form of dementia. Due to rising life expectancies, 础濒锄丑别颈尘别谤鈥檚 is on the increase and current drugs only slightly alleviate the symptoms of memory loss and confusion, without doing anything to slow the condition鈥檚 progress.
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A build-up of amyloid in the brain has been suspected as the root cause of 础濒锄丑别颈尘别谤鈥檚 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 础濒锄丑别颈尘别谤鈥檚 raise amyloid levels.
But the quest to develop amyloid-destroying drugs hasn鈥檛 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 础濒锄丑别颈尘别谤鈥檚 was even correct.
More recently, the amyloid story turned a corner. In 2021, a drug called aducanumab 鈥� which consists of antibodies that bind to amyloid 鈥� 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, 鈥渕omentous breakthrough鈥�. 鈥淚n 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,鈥� says at the UK鈥檚 础濒锄丑别颈尘别谤鈥檚 Society. 鈥淲e are in a new era.鈥�
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聽big enough to be noticeable by people with 础濒锄丑别颈尘别谤鈥檚 or their families. For instance, , those receiving the drug worsened by 1.2聽points on an 18-point scale used to rate dementia symptoms. Those who got a placebo worsened by 1.7聽points 鈥� just half a point more. Doctors have previously estimated that to people鈥檚 lives. A聽0.5-point difference is聽really undetectable, says at the University of Southern California, Los Angeles.
While the antibodies have been lauded as the first 鈥渄isease modifying鈥� 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 at University College London.
A spokesperson for lecanemab鈥檚 manufacturer, Eisai, says: 鈥淲e are confident that the results demonstrated by the study are clinically meaningful. For patients in the early 础濒锄丑别颈尘别谤鈥檚 stage, a change of score [of half a point] in the memory domain means progressing from benign forgetfulness to moderate memory loss.鈥� Donanemab鈥檚 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. 鈥淎pplication of such differences to a treatment group versus an individual patient level may be misleading.鈥�
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 . 鈥淗aving a kind of immune reaction to something in the wall of your blood vessel isn鈥檛 great for that blood vessel鈥檚 integrity,鈥� says Howard.
Yet this alone doesn鈥檛 have to be a dealbreaker for the drugs鈥� use, says 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 础濒锄丑别颈尘别谤鈥檚 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鈥檛 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鈥檛 yet gained the standard form of FDA approval, only the more tentative 鈥渁ccelerated approval鈥�.
The final FDA decision on lecanemab is due in July. Until then, Medicaid and Medicare 鈥� the country鈥檚 two biggest public health insurers 鈥� 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鈥� use seem more remote. It doesn鈥檛 help that they wouldn鈥檛 slot neatly into current healthcare for people with dementia. The drugs are designed to be given early in the condition鈥檚 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鈥� barely detectable effects on memory, such arguments seem unlikely to sway NICE, says Howard.
All these issues are leaving people affected by 础濒锄丑别颈尘别谤鈥檚 and their families in a kind of limbo. There are news reports of breakthrough treatments, yet, in practice, the drugs aren鈥檛 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聽somewhat of an advance for聽础濒锄丑别颈尘别谤鈥檚 science, by confirming that the protein plays a role in the condition. 鈥淭his is positive news, but it is a tiny, incremental step that probably isn鈥檛 going to have a big impact in聽the clinic,鈥� he says. 鈥淚n 10 years鈥� time, I鈥檒l be very surprised if lots of聽patients are on these drugs.鈥�
Genetic minefield
If new 础濒锄丑别颈尘别谤鈥檚 drugs start being used, there will probably be an uptake of a particular genetic test, which can have disturbing repercussions. The test involves the gene聽ApoE, a variant of which puts people at higher risk of 础濒锄丑别颈尘别谤鈥檚: people with one copy have about double the relative risk as those without, while two copies raises the risk approximately 10-fold.
Until now, there was little reason to take the test because there are no preventative treatments for 础濒锄丑别颈尘别谤鈥檚 and it is debatable whether people would want to know that they carry this variant, which also raises the risk of brain swelling. But one drug manufacturer, Eisai, recommends that those with 础濒锄丑别颈尘别谤鈥檚 take the test to learn if they have the variant and could therefore be at higher risk of brain swelling before they begin the treatments, which can cause this problem as a side effect.
If they learn they have the variant, this would have consequences for their relatives: if a parent has two copies of the variant, their child must have one copy and may have two. Finding this out could affect their prospects of getting health or life insurance in some countries. US rules are unclear on whether knowledge of a relative鈥檚 genetic test results has to be disclosed to insurers, says Madhav Thambisetty at the National Institutes of Health in Baltimore, Maryland. 鈥淚t鈥檚 an ethical and legal grey area.鈥�.
