New Alzheimer’s drugs don’t deserve hype – here’s why
A standout childhood memory is of my grandparents living with dementia and then dying of it.
As is usual with dementia, there was a double whammy: watching my grandparents lose their identity and seeing the suffering of those closest to them.
When I was in my 20’s as an intern in a specialist dementia ward, I saw the same stories play out in family after family and felt largely powerless to help.
Now in my 30s, I’m doing public health research to find out what we can do to prevent, delay or improve dementia – the number one killer in England.
Of course, this makes me desperate for good news about treatment options for Alzheimer’s disease – the main cause of dementia.
Name three drugs (aducanumab (trade name Aduhelm), lecanemab (Leqembi), and donanemab) that remove amyloid, the protein thought to cause Alzheimer’s disease.
Unlike their many predecessors, which also successfully cleared amyloid from the brain, these drugs were the first to slow cognitive decline.
This breakthrough has been hailed as “the beginning of the end for Alzheimer’s disease,” but how useful will these drugs be?
There are four major shortcomings to consider:
- Tiny benefits: In the donanemab study, the number of people taking the drug worsened an average of 10 points on a 144-point cognitive scale. The placebo group dropped 13 points.
Consistent with the patterns seen in the studies of the other two drugs, this tells us that all groups in all of these studies experienced a decrease and the decrease that was avoided by taking the drug – in this case donanemab – (three points) , was much smaller than the magnitude of the decline that occurred (ten points).
The difference in the magnitude of the decline was so small that it would probably be imperceptible to the doctors treating these patients.
- Side effects: Regular magnetic resonance imaging (MRI) scans showed signs of brain bleeding in one in six people taking lecanemab and brain swelling in one in eight people.
Regular scans can sometimes reveal these pathologies in dementia patients. In fact, 1 in 11 participants in the placebo group had bleeding, while 1 in 59 had swelling.
In most people, these events were only detectable by MRI and not by the appearance of specific symptoms.
However, the effects of the brain damage caused by this drug, particularly the long-term effects, are unknown.
Unfortunately, there have also been some deaths attributed to these drugs.
- Very expensive: Aducanumab was marketed in the US at US$45,000 (£35,000) per patient per year (later reduced to US$20,000 to increase demand), and lecanemab at US$26,500.
This only applies to the drug itself. Healthcare systems must also pay for additional scans for proficiency testing, monitoring and treatment of side effects, and staff to run infusion clinics.
The donanemab study suggested that treatment could be stopped if brain scans showed adequate amyloid clearance.
However, we don’t know if the amyloid will come back after some time. Regular monitoring for amyloid recurrence and repeated courses of treatment would incur additional costs.
There are other imperatives for the patients: a doctor’s visit every two to four weeks for drug infusions, regular monitoring and fear of side effects.
- Highly Selective Studies: It is accepted that not every study “effectiveness” (the effect observed in a specific study context and designed to reduce the likelihood that treatments will work, such as including only uncomplicated cases) to maximize, into a clinical “efficacy” (the effect) This can be observed when administering drugs to comparatively more complex patients in busy, real-world clinical settings.
This is worrying because there is little room for maneuver before the effects become imperceptible. And although this is the case with all diseases, Alzheimer’s may be an extreme example.
For every ten patients that doctors thought might be eligible for these studies, seven or eight were turned down.
People with brain pathologies other than amyloid, such as vascular damage or Lewy bodies, and people with significant other medical conditions that may have clouded the study results and increased the risk of side effects were excluded.
If drug eligibility is restricted to being admitted to the study, very few people are eligible. If eligibility is broader, the already small effects are likely to be even smaller and the side effects more pronounced.
Pervasive flaws
there is more The studies selected people in the earliest stages of the disease – that is, when symptoms had only recently developed – and were able to successfully clear amyloid, yet the patients’ condition regressed almost as quickly.
That’s why researchers inevitably ask themselves: maybe we need to start the drugs even earlier? But how?
Participants in the studies were, on average, five to 10 years younger than most people in the US and UK when they were diagnosed with Alzheimer’s.
And getting people to develop the disease earlier is problematic because most people with amyloid but no cognitive symptoms do not develop dementia before they die.
Unfortunately, I don’t think these drugs can make much of a difference for people who have Alzheimer’s either now or in the future.
Also, despite decades of costly studies and patient sacrifice, the shortcomings are so serious that I think it’s time to take off the amyloid blinders and prioritize research into other, neglected options for treating dementia.
This isn’t the beginning of the end for Alzheimer’s disease, but perhaps it should be the end of the anti-amyloid pathway.
Written by Sebastian Walsh. The conversation.
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