With Europe’s population living longer, the quest for new Alzheimer’s disease (AD) therapies has never been more urgent. Researchers hope that figuring out which genes and environmental factors trigger the illness will deliver drugs that prevent serious memory loss.
‘It’s complex,’ said Koen De Witte, Managing Director of reMYND, a university spin-off company based in Belgium and one of the four small to medium size enterprises (SMEs) involved in AgedBrainSYSBIO. ‘The development of AD is a multifaceted interplay between people’s genetic predisposition – their genes giving them a higher or lower chance of getting the disease – and environmental factors, of which many, including heavy metals, pesticides, smoking, physical inactivity, and an unbalanced diet, have been more or less tightly associated with the onset of Alzheimer's disease.’
De Witte compares this predisposition to AD to, for instance, obesity: a small number of people have genes that mean they are almost certain to become obese. But for most, obesity is a combination of their genes and taking in more calories than they burn.
The obesity equation is relatively simple compared to AD – eat less, exercise more and your chances of becoming morbidly obese decline. ‘With AD, we know little about what triggers the disease and we are still working out the relative importance of each of the genes that have been shown to play a role.’
No single Alzheimer's gene
Unravelling the mystery could eventually allow people to estimate their risk of developing the disease. This could involve a combination of a blood test, a spinal fluid test, and perhaps brain imaging. The trouble is that, without effective ways to prevent or treat AD, there is little value in knowing you are likely to suffer from the disease.
‘Most of the treatments available today can treat the symptoms somewhat, but the underlying degeneration of the brain continues. The focus now is on slowing disease progression.’
Koen De Witte, Managing Director of reMYND
One thing is for certain, there is no single ‘Alzheimer’s gene’. Several genes have been identified as being directly related to the brain cell dysfunction and death seen in people with early-onset AD, which strikes people younger than 65. However, there may be a dozen or more involved in late-onset AD, which is considerably more common.
Some of these genes influence the production of two known misshapen 'sticky' proteins, called beta-amyloid and tau, which accumulate in brain cells and are associated with brain cell toxicity in people suffering from dementia. In recent decades, researchers keen on developing new drugs have turned their attention to these abnormal sticky proteins and to the loss of brain cells with which they have been linked.
If a drug or vaccine could be found which could disrupt this process of cell death, the memory loss associated with AD could be halted. So the theory goes.
In their lab on the edge of Leuven, Belgium, scientists at reMYND are using specially bred mice to test potential medicines which they hope might stop or slow the development of AD. The mice all have a familial gene causing them to develop a disease that is very similar to early-onset dementia so they are ideal for testing whether a drug can disrupt the decline associated with AD.
Slowing down memory loss
‘Most of the treatments available today can treat the symptoms somewhat, but the underlying degeneration of the brain continues. The focus now is on slowing disease progression. The mice used in the reMYND lab mimic the AD process, so we test whether drugs can prevent the memory loss in mice and the associated development of pathology,’ explained De Witte.
Koen De Witte is Managing Director of the reMYND lab. © Koen De WitteIf AD were diagnosed early, perhaps even before symptoms had begun, stopping the disease from getting worse would have a huge impact on quality of life. But, can De Witte ever envisage the process of brain cell loss being reversed?
‘Preventing healthy brain cells in a patient’s brain from becoming diseased would be a major breakthrough, which we should achieve in the coming decade, especially when combined with early diagnosis,’ he said.
‘Restoring cell function, let alone reversing cell loss, would be great, but I’m not sure we’re getting there any time soon. There are typically some cells that may not be functioning but are not yet dead. Perhaps function could be restored to those cells. At the moment, if we could slow down memory loss by 50 %, it would be seen as a major breakthrough.’
The reMYND team is part of the EU-funded AgedBrainSYSBIO project that studies the ageing brain. De Witte hopes reMYND’s mouse models could help to deepen the understanding not just of the relatively rare early-onset AD, which has a strong genetic cause, but perhaps of the more common forms of the disease that strike later in life and may be triggered by a host of genetic and environmental factors.
Growing momentum for AD research
‘We are not only looking for better treatments for people with only this particular mutation of the gene concerned,’ De Witte said. ‘It is expected that the animal models mimicking the genetic early-onset of AD will be instructive for understanding the more common form of AD, which typically develops at an older age. In other words, the genetic model is an anchor point for understanding the disease.’
So what of the future? De Witte acknowledges that the short-term prospects are not encouraging, but the concerted effort in Europe and elsewhere offers hope of advances in diagnostics and therapeutics.
‘Based on the products currently in advanced stages of clinical trials, my personal view is that any new treatment emerging in the next five years will be a good start but will only have a limited effect. But, in 5 to 15 years, there could be major breakthroughs,’ he said.
‘In Europe and the US there is growing momentum on AD research. We have enough anchor points to be able to build something on existing knowledge.’
The team of the reMYND lab is part of the EU-funded AgedBrainSYSBIO project, a multidisciplinary consortium of 14 academic and industrial internationally-renowned research teams from Belgium, Estonia, France, Germany, United Kingdom, Israel and Switzerland, that are combining integrated systems biology and comparative genomics approaches to study the ageing brain. It is hoped that the project will identify and validate new molecular targets and biomarkers associated with late-onset Alzheimer’s disease (AD) and eventually contribute to slowing the progression of Alzheimer’s disease.
Professor Michel Simonneau of the École Normale Supérieure de Cachan, INSERM (the French National Institute of Health and Medical Research) who co-ordinates AgedBrainSYSBIO said, ‘This ambitious project integrates numerous European initiatives as well as national research programmes, which address the scientific and societal challenge of neurodegenerative diseases. The link between academia and industry is the driving force of the work and in the end will hopefully benefit us all.’
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