Last updated January 11, 2018 at 10:28 am
Science Update is a series tackling some of the most important topics in science and aims to provide the current research behind these subjects. In this installment Lila Landowski updates us on the state of the science on prevention and treatment of dementia.
“SUBSTANCE SHOWN TO CURE ALZHEIMER’S DISEASE!”
How many times have you seen sensationalist headlines like the above?
In light of this, many would be surprised to find that there is still no cure or disease-slowing drug for Alzheimer’s Disease on the market today. But this is not for want of trying: there have been thousands of promising drugs screened pre-clinically, and of the of the 400+ agents that made it to clinical trials, all disease-modifying drugs were unsuccessful – either due to lack of efficacy or toxicity. Currently the only available therapies for Alzheimer’s Disease are aimed at symptom control.
Dementia is a syndrome that has many different causes, with Alzheimer’s Disease being the most common. Dementia is the 7th biggest killer worldwide, but perhaps more worrying are the Australian statistics: Dementia is the leading cause of death in women, and the third most common cause of death in men. Age is the biggest risk factor for dementia, and given that we live in an ageing population, dementia cases are set to almost triple by 2050.
The realisation that dementia is fatal surprises many. The brain provides the instructions that tell our body parts what to do, as well as generate our behaviours, personality and cognition (our ability to think, understand and do things). When a person has dementia, neurons in various parts of their brain stop communicating effectively, and gradually break down and die. In the early stages of dementia, a person may have issues with only a single domain such as memory, attention, or personality. As dementia progresses, more areas of the brain will succumb to disease, and affected people will ultimately lose the ability to speak, eat, and function independently.
Drugs in development
There are more than 100 new drugs currently being tested for Alzheimer’s Disease. The most promising dementia drug undergoing clinical trials in Australia is Aducanumab, a drug that helps clear away beta-amyloid, the proteins thought to cause Alzheimer’s Disease. The results from phase III trials are expected in 2020, but the phase II trial (set up to determine the dosing and safety of the therapy, rather than its efficacy), demonstrated a modest improvement in cognitive function in those that underwent a full year of treatment. The effects of Aducanumab appear to be dose dependent. However, higher doses were associated with more risk of side effects.
The most common adverse event was the detection of abnormalities in brain-imaging scans, followed by headache. Researchers monitor brain structure closely through brain scans, as some participants in previous failed Alzheimer’s antibody trials have died because of brain bleeds and fluid buildup. Forty of the 165 patients discontinued treatment, most commonly due to these side effects. Side effects were common in all groups, including the placebo group.
Like the majority of putative dementia drugs tested to date, Aducanumab is an immunotherapy that clears up amyloid beta plaques. Amyloid beta plaques are a hallmark feature in the brains of persons with Alzheimer’s Disease. However – we do not know whether amyloid beta is a cause of Alzheimer’s disease, a protective response, or simply a by-product of earlier processes related to the disease. The number of amyloid beta plaques do not correlate to the severity of the disease between individuals. Indeed, not all people with amyloid beta plaques will have Alzheimer’s disease.
Another more controversial therapy proposed for Alzheimer’s Disease is the use of plasma transfusions from young individuals to those with dementia. All initial clinical trials first set out to assess the safety of the procedure rather than its efficacy, but in this instance the investigators not only demonstrated safety, but detected a significant benefit. Unlike Aducanumab, the benefit was not in terms of cognition, but in the ability of persons with dementia to perform various activities of daily living. The scientific community will watch future trials unfold with interest.
With the benefit of hindsight, one day we will look to this era of failed clinical trials for Alzheimer’s Disease as the hurdle that we persisted through and overcame, or as the wrong hypothesis that derailed decades of progress. Researchers learn from every unsuccessful trial, each helping pave the way forward for future treatments. These ongoing studies give us hope, because there is currently no cure for Alzheimer’s disease and the present trials are the closest we have come to a therapy after decades of fervent research.
A beginners guide to Dementia
Our brain provides the instructions that tell our body parts what to do, as well as generate all of our complex behaviours, our personality and cognition (our ability to think, understand and do things). When a person has dementia, neurons in various parts of their brain stop communicating properly, and gradually break down and die.
The symptoms a person with dementia develops will depend on what part of the brain is affected. Certain causes of dementia will preferentially affect different parts of the brain. For example, a person with Alzheimer’s Disease will predominantly have degeneration in the hippocampus and the entorhinal cortex. The hippocampus is involved in making memories and keeping track of what you do from minute-to-minute, and the entorhinal cortex a specialised part of the brain that works with the hippocampus; taking in input from all our different sensory processes to help orientate us in space and time, and to help us form declarative memories: that is, things like facts, knowledge, and memories of events.
What happens in the brain of a person with Lewy Body dementia is a little less well defined, though it includes damage in a slightly different part of the hippocampus, and a loss of dopamine and acetylcholine producing neurons. These neurons are important for various aspects of movement, cognition and visual perception. Because of this, they might experience hallucinations and difficulties with movement.
A person with Frontotemporal dementia will have degeneration that affects the frontal and temporal lobes of the brain, though the exact location can vary. The frontal lobe is responsible for much of our behaviour- our personality, our ability to problem solve and make judgements – and/or the temporal lobe (which actually contains the hippocampus), is the part of the brain that helps us process faces and scenes, as well as form memories. People with frontal lobe dementia often have some characteristic changes in behaviour, but more on that soon. To make things more complex, you might have more than just one type of dementia.
Living with dementia
Everyone is a little different, so people with the same cause of dementia won’t necessarily have all the same symptoms. One of the most common things that happens is that there is memory loss due to damage of the hippocampus. It won’t necessarily be the first thing that happens, but it often is one of the first things people notice. You might have trouble keeping track of what you are doing, or forming new memories. This can actually be quite terrifying. Imagine being somewhere and suddenly being unable to remember where you are or how you got there, and not knowing what year it was?
A person with dementia might be feeling this all the time. They might also start losing more and more of their older memories, as the disease erodes the neurons storing long term memories stored in various places in the cortex. This means their most recent recollections might be from years ago, so they might feel like they must be existing in that time. Imagine talking to your friends thinking it was the year 1990, and then having them tell you that you are wrong, and that everything you know is wrong. It would be terrifying. They don’t remember, because as far as they know, none of these things have happened yet. This is why we shouldn’t try to correct them. Let them enjoy their reality.
Eventually, the disease will spread through the brain and more and more areas will be affected. For example, the neurons in part of the brain involved in recognising faces (called the fusiform gyrus) might break down, and a person with dementia mightn’t be able to recognise you – even though they still remember who you are. If you talk to a person with dementia, it is helpful to reintroduce yourself, just in case they are having trouble working out what they can see. But don’t take it personally if your name doesn’t ring a bell. It isn’t their fault that the dementia has stolen their memories.
Sometimes, for a person with dementia, the parts of the brain involved in our ability to make judgements and decide what is socially acceptable might break down (for example, the ventromedial region of the prefrontal cortex). So a person with dementia may act on their impulses or vocalise their opinions or thoughts without realising how awkward or inappropriate they are.
Research efforts are under way to develop better ways to care for affected people and improve support for their families, friends and caregivers. Simple tools can provide a very effective way to improve the quality of care of people with dementia, and enhance interactions with staff during a hospital stay. Other key concerns are the need to improve the quality of life for people with dementia. We can all help, through education and understanding.
To learn more about dementia, you can sign up for free multi-award winning courses here.