This post is longer than what I usually write, but humour me on this occasion, as it’s

After caring for my mum at home for the previous four years, she had recently collapsed and we had no choice but to put her into an aged care facility. I was beginning to question more than ever about what caused Alzheimer’s, and the following year I began to question how I could help …

As a child I remember my mother telling me that when she became old she never wanted to be put in a nursing home. I emphatically promised her that this would never happen and I would always look after her. Six months ago I broke that promise and I am haunted each day by what I had to do. But I had no choice. I have been robbed of my mother by the slow, degenerative, and to date, incurable disease, known to medicine as Alzheimer’s disease (AD), but by those whose loved ones are afflicted, as the ‘living death’. We lose the person we love one bit at a time.

The root cause of many illnesses has been extensively researched and, in some cases, clear correlations have been made and risk factors identified by the medical community. Smoking for example is the cause of most cases of lung cancer, with smokers around 20 times more likely to develop the disease than non-smokers. The brain however is an incredibly complex organ and the function and physiological mechanisms associated with its ‘normal’ healthy state are impossibly difficult to understand; the mechanisms of a diseased brain, even more so.

Australian Dementia Statistics in 2009

Over the past four years since learning of my mother’s diagnosis, I have been surprised by the general lack of understanding of the disease by the public. As cancer and AIDS were once unmentionable diseases, now AD appears to be stigmatised. Yet it causes the highest number of deaths in Australia, only currently surpassed by cardiovascular disease and some forms of cancer, depending on gender. While cardiovascular disease has been reduced over the past decade, the Australian Bureau of Statistics (ABS) notes an almost doubling of dementia cases within the same period. Neurodegenerative disease is set to become one of the largest socioeconomic problems the world has ever faced as our population ages and life expectancy increases, without significant medical breakthroughs in the diagnosis and early intervention of the disease. Here are just some of the findings from a 2009 report* commissioned by the Alzheimer’s Association.

• There are currently around 245,000¹ people diagnosed with AD in Australia. By mid-century, we will have over 1.13 million Australians with dementia
• Dementia is the leading single cause of disability in older Australians (aged 65 years or older)
• It is one of the fastest growing sources of major disease burden, overtaking coronary heart disease in its total wellbeing cost by 2023
• Dementia will become the third greatest source of health and residential aged care spending within about two decades – costing around 1% of GDP
• By the 2060s, spending on dementia is set to outstrip that of any other health condition. It is projected to be $83 billion (in 2006-07 dollars), representing around 11% of the entire health and residential aged care sector spending.

These projections highlight the pressing need to increase awareness of the disease and funding into research for simple and early diagnostic procedures, prevention and early intervention, not to mention care and financial provisioning. If the onset of dementia was delayed by just five years (in what seems to be a strategy pursued by the experts rather than aiming at a complete cure), there would be a 50% reduction in new cases each year and a saving of $14.5 billion by 2020, according to the report.

What causes Alzheimer’s Disease?  Who is most likely to get it?

One of the most common misconceptions about AD is that a sufferer ‘just’ becomes forgetful and eventually loses their memory. While this is one part of the disease, it is in fact multi-faceted. AD can start years before symptoms begin to present, but when they do they can take many forms over the different stages including apathy, confusion, anxiety, challenging or aggressive behaviours and lack of personal care. As the disease progresses, memory loss and attention worsens, implicit memory is lost – which is our body’s memory of how to do things such as drinking from a cup and eventually the brain degenerates to a point where the ability to speak, eat and swallow is lost and the disease becomes terminal.

So who is most likely to get it? What causes AD? What can you do to prevent it? With these questions in mind and to learn more about the research being conducted at my Alma Mater, The University of Sydney, I went to speak with two of the world’s leading authorities on the underlying pathological mechanisms of neurodegenerative disease, at the University’s Brain and Mind Research Institute (BMRI). Both kindly gave of their valuable time and knowledge. Professor Jürgen Götz¹ is the Director of the Alzheimer’s and Parkinson’s Laboratory and Dr. Lars Ittner² is Head of the Laboratory for Translational Neurodegeneration at BMRI.

Alzheimer’s is not a selective disease. US presidents (Ronald Reagan), UK Prime ministers (Harold Wilson), actors (Rita Hayworth) and authors (Terry Pratchett) have all succumbed. When I asked whether certain groups of people or personality types had a higher predisposition to the disease, Professor Götz said he was not aware of any major differences between ethnicities and Dr. Ittner explained when they overlaid a world map of AD cases it “pretty much added up” with the world map of life expectancy. In countries where a lower number of cases have been reported, such as India, it appears to be due to the lack of reporting from rural and underdeveloped areas. Typically people don’t reach the age when symptoms would usually begin to show, unlike developed countries with higher life expectancies.

Diet and level of exercise do vary between different ethnic and socioeconomic groups and there are implications that both of these external factors can impact on the early onset of AD. “Omega 3 fatty acids in the diet or certain vitamins and antioxidants, exercise and diet seem to play a role in dementia,” Professor Götz explained. Any links to the onset of AD from exposure to heavy metals, plastic and toxic chemicals however is more difficult to prove, due a lack of control groups, since world-wide we are all exposed to these substances to varying degrees. Dr. Ittner explained that exercise is very important and its effect is reproducible in all animals. “If they get more physical exercise they don’t develop this pathology [for AD]”, he said.

My aunt developed AD a few years after the death of her husband of 60 years and I’ve often wondered whether there is a relationship between mental trauma and the onset of AD. Dr. Ittner said the link between mental stress and AD is not unheard of, but he said, “we don’t understand what is going on in the mental stress situation”, which is the biggest problem in trying to find a correlation. There have been many documented cases of physical trauma leading to AD. Peripheral operations, such as knee and hip replacements have led in some cases to patients waking up demented after the surgery. In these cases it is believed, but not proven, that the anaesthetic has tripped off the pathology of the disease.

Genetic Link to Alzheimer’s

What is becoming more widely understood and accepted about AD from the research conducted by different groups around the world, is that AD has a huge genetic component. While most cases of AD are still what is called  sporadic, which means there are no familial cases or genetic predisposition, there are an estimated 1% to 3% of cases where the disease has been inherited. In these cases Professor Götz explained, “the presence of the autosomal dominantly inherited genes, that account for around 1% of all cases, inevitably leads to AD.” He said that there “are also risk genes known, for example Apolipoprotein E (APOE) and when you are a carrier of the e4 variant this does not mean that you will necessarily develop AD, but your risk is six- to eight-fold higher than in the normal population.” “Genetic cases are quite rare”, Professor Götz reassured me. There are genetic tests available to determine whether you have one of the dominant mutations, but there are still many more genes which have been suggested may or may not play a role in developing AD.

While APOE and advancing age are confirmed risk factors for AD, the area where Professor Götz and Dr. Ittner are developing ground breaking work (a term Dr. Ittner does not care for, but which really cannot be described in any other way) is determining the mechanism which underlies the pathology of AD. Only with this understanding will treatments be possible to ‘turn off’ the disease at an early onset or even prevent its onset through developing therapies which exploit the knowledge of this mechanism. An Alzheimer’s brain is characterised by two types of lesions, which were discovered over 100 years ago by the German psychiatrist and neuropathologist, Aloysius Alzheimer. Around 25 years ago the proteins making up these lesions were discovered to be amyloid-ß (Aß) which forms plaques, and tau which is deposited within neurons in the form of neurofibrillary tangles. Dr. Ittner explained, “There was good evidence from previous work done that there is a link between these two proteins, but how mechanistically it worked was unclear.”

Ground-breaking research

The main toxicity of Aß was previously known to be at the receptive side of a neuron, while tau was localised to the axons or the long processors of the neurons. Due to the spatial separation it was thought there was no interaction between the two. Without explaining the full technicalities, Götz and Ittner brought the two in proximity and showed how they actually link and which molecules and receptors are involved. From this point Professor Götz explained, “We took on an approach which was used in strokes and translated it to our Aß model, modified it quite a bit and basically infused an interfering substance, which modulates this pathway we have identified, into the brains of mice and that completely prevented the pathology, so it switched off. The transgenic mice which were born with AD no longer died early or showed any kind of memory deficit.”

The two basic tools for looking at AD are animal and in vitro (cell culture) models. The team at BMRI specialises in mice models working mainly with this species, although for the past year they have also been modelling tiny round worms which are both cheaper and easier from an ethical aspect. I asked to what extent mice model human pathology and Professor Götz said, “Obviously only to some degree because in humans it takes 40, 50, 60 years to develop disease.” To carry out any meaningful research the process needs to be sped up, which is what makes mice such ideal candidates to use in research. “Mice I think are still the best model to work with and also in our field they have contributed a lot to understanding the principle pathological mechanisms, but also helped design treatment strategies, for example the current immunisation strategies are all based on mouse work.”

The one thing both Götz and Ittner emphasized, was the importance of treating AD early on in its onset to prevent its development. Late in the disease the neurons and their connections have already been lost and are hard to replace. While stem cell therapy could be used to bring out new neurons, it would not be of any use as the new neurons would have no memory – they wouldn’t ‘know’ anything. “Therapy must be in the very early stages of the disease, which calls for the people who develop a detection method,” Dr. Ittner said.

While the pharmaceutical industry has yet to come up with any effective treatment which target Aß, through their latest research Götz and Ittner have shown that even if Aß is around in the brain and continues to accumulate, the toxicity can be rescued to prevent it from interfering at a local level.

Will we ever have a cure for Alzheimer’s?

Looking to the future I asked both researchers whether they believed a cure would ever be developed for AD. Professor Götz believes that the future treatment for AD will be in the realm of disease modifying drugs which would delay the onset of the disease. “Let’s say instead of having an age of onset at 70, if you would develop AD at 90, because most of us don’t become 90 years of age, we would effectively not develop the disease,” he explained. It seems to be a more realistic view to slow down rather than prevent the disease process, but it will be reliant upon tools to diagnose at early onset. Teams of researchers are working around the world on biomarkers in blood tests, because there are still no simple methods to definitively determine that you have AD.

Dr. Ittner said, “The end story will be that the treatment will be with not only one approach, it will always be a combination of treatments.” This is because the mechanism involved with AD is so complex and cannot be solved by modifying just one part.

Neurodegenerative diseases currently receive a fraction of the funding given to other health groups such as those working in the cancer field and research in this area is costly. Working with mice for example is expensive. Professor Götz explained that it costs approximately $200,000 each year only to maintain their colony of around 3,000 genetically modified (transgenic) mice. The research of Professor Götz and Dr Ittner needs financial donations to secure the resources that will enable further progress to be made to cure and alleviate diseases of the brain and mind which now account for over 40% of all illness.

While there is currently no cure for AD, care is becoming a lot better for patients and their families with greater understanding of the disease and we can find hope from the research being carried out world-wide to find ways to prevent and manage this crippling and devastating disease.

…………

Originally published in HarbourView magazine in February, 2011.

* Access Economics, Keeping dementia front of mind: incidence and prevalence 2009, August 2009
¹ Professor Jürgen Götz is now the Foundation Chair of Dementia Research and Director of the Clem Jones Centre for Ageing Dementia Research at the Queensland Brain Institute (University of Queensland)
² Dr Lars Ittner is now the Director of the Dementia Research Centre and Professor in the Department of Biomedical Sciences of the Faculty of Medicine, Health and Human Sciences (Macquarie University)