Thursday, 13 February 2014

Dementia: is a cure around the corner?

by Jonathan Smith

Amidst regular breaking news stories of promising developments in the fight against dementia, we’re still no closer to being able to stop its progression. The company that finds a cure for dementia would not only start a revolution in treatments, but also make huge profits doing so. If this is the case, then why are we still waiting for effective treatments after decades of research into this oppressive disease? 

Prevalence and treatments for dementia

It’s no secret that dementia is a widespread condition. According to the Alzheimer’s Society, the established prevalence of dementia for 70-79 years is 1 in 25. For those over 80, the rate soars to 1 in 6. Considering the colossal cost to healthcare systems worldwide, the potential benefits of finding an effective treatment far outweigh the cost of making it. However, the current treatments available for dementia are minimal. Drugs such as Donepezil, Galantamine and Memantine serve to temporarily reduce the cognitive impairment caused by Alzheimer’s Disease, but do not target the pathology directly. This means that the more advanced cases eventually cease responding to treatment altogether. The brain tissue is just too damaged to salvage by then. What is desperately needed is a treatment that can actually alter the disease itself, resulting in a slower or even halted progression.

It’s not as if pharmaceutical companies haven’t been trying to find disease-modifying treatments of course. Last year the drug Semagecestat failed a massive clinical trial in Alzheimer’s Disease patients. It turned out that patients actually got worse with the drug! In the same year, the catchily-named drug LY2886721 was withdrawn from development due to abnormal liver tests in some trial patients. And failures are costly in the pharmaceutical business. Getting a drug to market can cost millions of pounds and can take over a decade for a company. Thus in the UK at least, industrial research into dementia treatments is getting less funding than ever. This still leaves the question: Why have the drugs failed to work? 

Understanding the neuropathology in dementia

The only simple answer so far is that, being a neurological disease, dementia is an extremely complex puzzle to unravel. Take Alzheimer’s Disease for example. A popular hypothesis of its origin is called the Amyloid Cascade Hypothesis. This suggests that the protein Amyloid-beta starts to get produced abnormally in the brain and clumps together outside cells, gradually causing neurons to malfunction and degenerate, resulting in the symptoms we see in Alzheimer’s Disease. One key piece of evidence for this is that a small proportion of patients get early-onset Alzheimer’s Disease and they all have hereditary mutations causing huge amounts of amyloid-beta production. Not only that, but Down’s Syndrome is also associated with amyloid-beta and guess what? Down’s Syndrome sufferers have a high risk of developing Alzheimer’s Disease. From this evidence, it appeared that a good way to slow Alzheimer’s Disease is by reducing the amyloid-beta production in the brain. As shown by Semagecestat and other failed amyloid-beta-modifying compounds, it turned out to be not that simple.

For one thing, Amyloid-beta is not the only factor to consider in Alzheimer’s Disease. There are many other hypotheses regarding other proteins and cellular systems involved in the symptoms of Alzheimer’s Disease. The result is a rather confusing jumble of different pathologies that neatly overlap with many other types of dementia, such as Vascular Dementia. Additionally, the stage of dementia is a massive factor. Current treatments stop working because there is so much damage to our brain tissue. Perhaps this is also the case with disease-modifying treatments? What if the only way to slow dementia is to tackle it before it causes extensive damage? To investigate this possibility, companies such as Merck are trialling previously failed drugs in patients with early-stage dementia. 

 Amyloid-beta protein
Another consideration is that the best way to trial a treatment early on is to test it in animals like mice and rats. In order to show its effects, we clearly need to give the animal dementia first. To give mice dementia, we first have to insert the mutated genes involved in amyloid-beta production into mice, straight from early-onset patients. As it turns out, it’s really difficult to make mice with Alzheimer’s Disease using genes selected from these patients. Firstly, the vast majority of Alzheimer’s sufferers have no such mutation and secondly, most mouse models of Alzheimer’s Disease show only bits of the condition. Some are cognitively impaired in some tests, others show amyloid-beta clumps, however, none show Alzheimer’s Disease in its entirety. It’s for this reason that many sensational headline cures for dementia found in rodents remain in rodents. It’s just not possible to perfectly translate a complex condition like dementia between rodents and humans. At least, not at the moment.

A cure is around a corner

Despite the recent setbacks in clinical trials, researchers are increasing our knowledge about developing treatments for dementia. Not only that, but steps are being made in improving the diagnosis of Alzheimer’s Disease early on, perhaps at a stage when a difference can be made to the outcome. As animal models of dementia are improved, we can begin to make better translation between animals and human patients. Furthermore, if as much funding for dementia is poured into these efforts as there is for cancer studies, we can increase the speed at which really effective treatments become available. For now, though, the best ways to reduce the risk of dementia are through a balanced diet, regular exercise and regular glasses of red wine!