Dementia: why don’t we have any treatments yet?
by Guest Author on 21 Sep 2017
Alois Alzheimer first described his eponymous disease a century ago, but there are still no effective treatments. For World Alzheimer’s Day, Professor Bart de Strooper, Director of the UK Dementia Research Institute, asks why that is, and tells us how that might all be about to change.
In the early 1900s, a German neurologist called Alois Alzheimer became obsessed with studying an Asylum patient in her 50s, who had started to show unusual behavioural changes, including short-term memory loss. After her death he examined her brain and discovered structures known as amyloid plaques and neurofibrillary tangles – the hallmarks of what became known as Alzheimer’s disease. So why, when we’ve known about the disease for so long, are there still no treatments?
A uniquely human organ
Until recently, there just hasn’t been enough invested in this area of science. Investment in dementia research is just a fraction of what has been ploughed into cancer research, for example. Only recently, with major initiatives like the Dementias Platform UK and the UK DRI has funding for dementia research increased. In fact, UK government funding has more than doubled between 2010 and 2015. So now that we are putting more brains on the problem, I hope that will help.
The human brain is a ‘black box’. It’s a very difficult organ to study. It’s the most uniquely human organ there is, very different to the brains of animals that we use as research models. We know much less about the brain and how it’s built than any other organ of the body. The problems and difficulties that have to be surpassed with dementia are larger than with other disease areas.
Perseverance with drug trials
We also need a change in approach from industry. Just 0.5% of compounds being developed as potential drugs for dementia have successfully reached patients, compared with an industry average of 4.1%. This is often because dementia drugs can fail to show promise in the early, preclinical testing phase. Developing a drug all the way through to market is costly. So pharma companies with an eye on their profit margin are quick to withdraw investment if a drug fails to show early results. But things are starting to pick up: since 2013, the number of Alzheimer’s drug trials has doubled.
A revolution in the offing
In the 1980s, when I was a young researcher, AIDS appeared out of the blue. People affected by the disease, and their families, mobilised and put the disease at the top of the political and pharmaceutical industry agenda. I’m excited to see that this kind of mobilisation is starting to happen now in the dementia world.
We are starting to see patients taking responsibility for the disease and even younger people are realising that eventually they too will be affected. With this revolution in society and with increased public investment in research we are finally getting the chance to make a difference.
Where are we now?
So what do we know for sure about the causes of Alzheimer’s disease? We know that, in rare cases, it is down to genetic mutations. This finding has been an important clue about what might be happening to cause the disease at the level of molecules within the brain.
We also know that there are risk factors, for example carrying a mutation on a gene called ApoE, and of course ageing. But there are also other risk factors that are within our power to modify and manage: up to 35%, according to a recent paper in The Lancet. Treating hearing loss in early life has been shown to reduce risk of getting dementia in old age. Lack of education in early life is linked with an increased risk. And then there are a few things that can be done by anybody – give up smoking, take enough exercise and keep your weight under control.
Dementia is slow and stealthy. Changes in brain chemistry that will ultimately lead to the disease can occur in early mid-life, as early as your forties. Decades before dementia symptoms appear, changes occur to cells in the brain. These changes involve not just brain cells but also the veins and arteries supplying them and cells responsible for inflammation. It’s a really complex process, but understanding it will offer a lot of opportunities to treat or slow it down.
Barking up the wrong tree?
For 25 years, scientists have been working with a theory about the cause of Alzheimer’s disease called the amyloid hypothesis which lays out a linear series of events which lead to the disease. It is becoming clear that this hypothesis is far too simple. Without doubt, amyloid protein plays a part in triggering the disease and we certainly should not stop trying to develop amyloid-lowering drugs – but it is now clear that it is not the only driver of the disease, as I discussed in a recent review.
At the UK DRI, I want our focus to be on how the different parts of the brain respond to changes in brain chemistry that trigger the dementias. If we can improve the brain’s natural defence mechanisms, or halt destructive reactions, for instance damage to the brain caused by immune cells, that would open a whole new window on treatments.
In the next few years I expect to see great progress in the diagnosis and classification of the different dementias, and we will get much better at predicting a person’s risk of getting them. I think we’ll also see society mobilise to cope with the risk factors that lie within our control. As a consequence, we will see the incidence of these diseases slowing – and just a one-year delay would prevent 9 million cases of dementia by 2050.
For Alzheimer’s disease in particular, anti-amyloid drugs will likely become part of the preventive efforts to halt dementia. But for other dementias it will take more time. The recent MRC-funded discovery of the atomic structure of tau filaments – another hallmark of neurodegenerative diseases – was a major breakthrough and I am interested to see what therapies aimed at the Tau protein will bring.
My biggest hope is an approach called nucleotide therapy. It uses short molecules to ‘stick’ to, and change the activity of, messenger molecules which help make brain proteins. It might provide a breakthrough that could make the dementias treatable within just a decade. If that does not work, I think we will have around 20 years of hard work in front of us, to generate an array of drugs that can then be used according to patient’s individual risk and disease – so-called ‘personalized medicine’.
Humanity has been able to control AIDS, to make major progress in curing cancer and other diseases, and to go to the moon and beyond. So why wouldn’t we be able to find a cure for this scourge that threatens our most precious gift – this beautiful organ that makes us who we are?
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