Photo by BruceBlaus, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons
Dear Readers, apologies for the second medical post in a row, but New Scientist has a very interesting article about the search for a cure for Alzheimer’s Disease so I thought I’d do a quick summary.
The lives of most people are touched in some way by dementia, and Alzheimer’s counts for 60 to 80 percent of cases. There have been drugs to slow the progression of the disease, but they are not without side effects: in the UK, NICE (The National Institute for Health and Care Excellence) rejected a drug called lecanemab on the grounds that the benefits were too few, the risks too high (brain swelling and bleeding) and the cost too high (£20,000 per patient per year). In trials, 12 percent of people taking lecanemab (which has to be administered in hospital by infusion every two weeks) suffered serious side effects. In trials, the drug was shown to slow the progression of Alzheimer’s by about 27 percent.
What Causes Alzheimer’s Disease?
The actual cause of Alzheimer’s has been controversial over the years, but scientists are gradually coming to a consensus about two factors. The first (and probably the most well-known) is the presence of abnormal proteins in the brains: beta-amyloid and tau. Beta-amyloid is a perfectly normal protein in the brain, but in some situations it glues itself together to form plaques. These in turn cause what are known as ‘tau tangles’, where a second protein, tau, which helps to support the integrity of nerve cells, starts instead to break them down. With the nerves no longer able to communicate with one another, cognitive decline starts to occur.
The second factor is inflammation – it’s long been known that tau proteins cause inflammation in the brain, and we are learning more about the role of inflammation in many conditions, from heart disease to immune disorders.
What’s in Development?
Lecanemab uses what’s known as a monoclonal antibody – the drug targets beta-amyloid but only when it’s in a plaque, so the ‘normal’ beta-amyloid can go about its work. However, as a drug the chemical disintegrates quickly in the body (hence the need for regular infusions). Also, it doesn’t stimulate the immune system to make its own antibodies, so the effect is short-lived.
To get around these problems, there are a number of vaccines in development. One, UB-311, is about to go into a phase III clinical trial, and could be ready by 2030. It’s designed to be used with patients with mild Alzheimer’s, and in a trial in Taiwan it slowed cognitive decline by 50 percent, with no side effects. It targets the beta-amyloid plaques in the same way as lecanemab, but it’s much cheaper and easier to use – a patient would have 4 or 5 injections in the first year, with a booster every year after that. The antibodies in the vaccine seem to be much better at entering the brain than those in drugs, and they will also encourage the brain to make its own antibodies. Again, it only targets beta-amyloid that is in a plaque, leaving the ‘good stuff’ alone.
Of course, a lot of drugs fail at the final hurdle, because they don’t prove to be as effective as hoped, or because they have intolerable side effects, but this looks promising. There are four vaccines of this kind in development currently.
There are also some vaccines that aim to remove the tau protein, long thought to be the villain of the piece because of its role in damaging neurons and causing inflammation. It’s more difficult to target, however, because it ‘lives’ inside the neuron, rather than on the surface like beta-amyloid. However, the tau protein has an Achilles heel (not that it has a heel, or indeed any extremities, but you get the idea). At one stage in its life cycle, it dangles outside the nerve cell, where it can be targeted with another vaccine that’s in development, with the catchy name of ACI-35.030. It may well be that a multi-pronged attack might be able to target both tau and beta-amyloid proteins.
And then there’s the inflammation that results from the tau proteins, which some scientists propose is the major cause of Alzheimer’s. Howard Weiner’s team at Harvard Medical School are looking at a drug called foralumab, which was originally developed to help to treat multiple sclerosis and Crohn’s disease. It can be administered as a nasal spray – the drug stimulates T-cells, which are an important part of the immune system. The T-cells then head into the brain to dampen down any inflammation.
Prevention?
Prevention of Alzheimer’s has to be the ultimate aim of any scientist working in this field, and one interesting development is a blood test that can detect the signs of tau tangles 20 years before any cognitive symptoms appear. A current trial of an anti-tau vaccine uses this blood test to identify people at risk, and this is confirmed with a PET scan to double-check if tau tangles are present in their brain. If so, they’re given the vaccine. Only time will tell how effective this is, but it does hold out the hope that it might be possible to ‘nip Alzheimer’s in the bud’.
Thoughts
About 55 million people worldwide are living with Alzheimer’s, and this number is expected to rise to 140 million people by 2050. Anything that can delay the onset of the disease gives people a chance to live healthy, happy lives for longer, and being able to detect Alzheimer’s early, and actually cure it, has to be the holy grail. But whatever is developed needs to be cheap enough to be given to everybody with the condition – the decision about lecanemab means that people who can afford £20,000 per year, and are prepared to risk the side-effects, can get the drug, whereas other people can’t.
Alzheimer’s is a disease that strikes people of every class and condition of life, and whilst there are amazing people who are living with the disease (such as Wendy Mitchell, whose book ‘Somebody That I Used to Know’ I highly recommend), this is a progressive condition with a devastating effect on every aspect of a person’s life. It is heartening to see how many scientists are working to try to find an answer, and which ever pharmaceutical company finds an effective answer first is likely to be both lauded and mega-profitable. Let’s hope that pricing and availability make it available for everyone who needs it.
And now, can the pharma companies please get stuck into researching alternative antibiotics as well? Not such a profitable area, for sure, but antibiotic-resistance will be, I believe, one of the biggest challenges of the next decades.