Given a sizeable portion of the institute I work in is dedicated to the investigation of Alzheimer’s Disease (AD) it would be remiss of me if I didn’t mention the exciting new paper on a potential treatment. Published this week in Nature was a paper that conducted a double-blind, placebo controlled trial of a drug called aducanumab.
AD is a particularly cruel disease. Over a couple of decades to just a few short years the disease slowly ravages your brain killing off neurons as it goes. The primary symptom is dementia which can manifest in a number of ways from memory impairment, thinking speed, mental agility, language, understanding and judgement. It is very common affecting an increasingly large fraction of the population with age. 1 in 30 people at the age of 70 will have dementia but that ratio rises to 1 in 3 by the time people are in their 90s. The disease is progressive and there is no cure.
Anyone who has witnessed or had to care for someone with dementia will understand the devastating toll it takes. The patient is robbed of their memories and personality, they are often confused and scared not even being able to recognise their own children and loved ones; eventually they lose the ability to care for themselves. As well as the impact on individuals and families the cost to society is enormous. We are all living longer these days, one third of babies born this decade are expected to live to the age of 100. In the UK alone there are nearly 1 million people with dementia and that number is rising by hundreds every day. By the middle of this century the number of dementia sufferers will double. It already costs the country more than £25 billion per year in medical costs, social care and lost productivity of loved ones who are disproportionately left to pick up the pieces of 24 hr care.
The scale of the problem is significant and treatments are urgently needed. It is disheartening to hear, then, that we still don’t even know the mechanism by which AD works. We know that parts of the brain degenerate but not why. We know that plaques build up in the brain made up of the sticky proteins Tau and amyloid-β but we don’t know whether these cause the problem or whether they are just another symptom of an underlying cause. There is an ongoing debate within the dementia research community about the causality of amyloid-β plaques in AD and the idea that they are, indeed, causal goes by the name of the amyloid hypothesis.
On their own molecules of the 42 amino acid long amyloid-β monomer are harmless, they circulate through our bodies carrying out various functions, we’re not actually 100% sure what their normal function is. Problems occur when there is either too much production of amyloid-β or too little clearance of it from our systems, again we’re not sure which. When at a higher concentration the monomers start to aggregate together into oligomers and, eventually, into fibrils and plaques. This in turn triggers an inflammatory response which leads to the build up of Tau plaques and tangles and the death of neurons. These molecular changes can onset two decades before the first cognitive symptoms appear.
Enter aducanumab. It is an antibody that binds extremely well to the amyloid-β oligomers and plaques but does not bind very well to the monomer form, thereby sparing whatever normal functions the molecule is carrying out. The trial was designed to test the ability of aducanumab to remove the toxic amyloid-β buildups inside the brain. Participants were split into four groups; one was a placebo group that received no drug and the other three received ever larger doses of the real thing. The trial was quite small with only 165 subjects and was not designed to test the effect on cognitive ability.
On the right you can see a set of brain scans one from each group of the trial. The left column is before treatment and the right column is after one year of monthly intravenous injections of aducanumab. You can see that the red and yellow diseased areas have got slightly larger in the person from the placebo group whilst in the others the number of plaques and fibrils has decreased. Importantly, there appears to be a dose response with a greater dose of the drug resulting in a greater removal of amyloid-β. This is good evidence that the drug is what has caused this improvement.
There are various projects now underway to specifically test for the impact of aducanumab on cognitive abilities though there are tantalising clues in the current Nature paper. Those in the placebo arm lost 3 points on a standardised cognitive test whilst those receiving the maximum dose lost just half a point. It must be stressed that these results are not definitive and we must await the result of the publications set up to test that specifically.
This early, preliminary evidence, however, is the most exciting news to hit the dementia scene in some time, possibly ever. Not only might it provide a definitive answer to the amyloid hypothesis but, for the first time, there is reasonable grounds to be hopeful for a real treatment in the not too distant future.
Note that this is not necessarily a cure. Even those on the highest dose declined though at a slower rate. Also, there are side effects to consider. Along with increased amyloid-β removal an increased dose of aducanumab resulted in an increase in amyloid-related imaging abnormalities (ARIA). In many people ARIA is symptomless but for others the outcome is transient headaches, visual disturbances and confusion caused by fluid buildup in the brain. These don’t tend to be severe, though, and often resolve themselves after a few months of treatment. We will need to find a sweet spot that balances maximum effectiveness of treatment against adverse side effects. It is also worth mentioning that with a group size as small as this it isn’t impossible that the effect will completely disappear once larger clinical trials report.
We have not cured Alzheimer’s Disease, but for the first time we have glimpsed the genuine prospect of a treatment that might significantly slow down its progression. Given that AD is mostly a disease of later life this could be highly significant. If the progression of dementia can be slowed from 5-10 years to something like 20 years then this could buy people time to live out their lives without losing their wits. Quality of life is so important, there’s no point living to 100 if you spend your last decade on this earth scared and confused. I think this new paper allows us to dare to hope.