 Hello, my name is Greg Sutherland. I'm a lecturer and researcher at the University of Sydney into brain diseases and as part of Brain Awareness Week in 2022. I'd like to talk to you about the mystery of Alzheimer's disease. So a little bit of background about myself before we start. I first trained as a veterinarian and I worked in equine practice for around about 10 years. I came across to Australia in 2003 and I'm now housed in a very impressive building called the Charles Perkins Centre on the Campedown campus at the University of Sydney. The CPC was built to look at diseases that are associated with metabolic syndromes like obesity and diabetes. And dementia interestingly is a brain disease that has quite a few risk factors in common with those types of diseases. My laboratory is housed up right on the top of the sixth floor, almost as far away as you can see from the front of the building that I face up towards the RPA Hospital. So one of the interesting things that you might not be aware of is that dementia, which includes Alzheimer's disease or Alzheimer's disease, Americans tend to refer to it as is the second leading cause of death in Australia. And if we look at female persons, it's actually the leading cause of death. And it's the first time in the statistics taken in 2018 that any disease has not a coronary heart disease from the most common cause of death in Australia. The reason why dementia is becoming so common is really our ageing population. And it's magnified by the fact that we don't have any useful treatments at the moment that can slow or stop the disease. But why don't we talk about Alzheimer's disease as being a great mystery or perhaps world's greatest detective story? A couple of the factors that contribute to this is, well, one, it involves the brain and that there's any organ system that we know as least about and then it is the human brain. The disease only manifests in the eighth or ninth decade with most people getting the disease at roundabout in the mid-80s. It's really, it really has a genetic cause. And what we call a pro-drain or the pre-symptomatic stage of the disease is probably longer than about 30 years. So all of this adds up to that a very subtle process could be operating over a long period of time to induce this disease and finding subtle processes is not what we're put at. Just on the right-hand side, we have a picture of our Alzheimer's with whom the disease was named after. In fact, it was named after by a general called Kregling who was in charge of Alzheimer's in some of his forms of years in medicine. And his first patient in which he described some of the brain pathology was a lady called Auguste Dieter and it would turn out many years later when genotyping technologies were more advanced that this lady had a mutation. So she was one of these rare genetic cases. And as you can see by her lifespan, she actually died very young for someone with Alzheimer's disease, which is consistent with her having a mutation. My job as a scientist or a neuropathology scientist is to try to understand how the features of this disease and the features within the brain relate to the development of the disease and to try and find treatment targets for that disease. So here on the left-hand side are some of the features that we see in Alzheimer's disease. So we are to remove at all topsy or post-mortem examination the brain of someone with Alzheimer's disease. We will notice that their brain is very much shrunken from someone who is normal for that age and gender. And when we talk about shrinkage, what we're talking about is these little gaps between the various parts of the brain called solcopy. They would normally, if you look at the part of this person's back of this person's brain here, you can see how tightly these gyri are opposed to each other. Whereas in someone that's lost a lot of their brain tissue, these solci or gaps between the two gyri expand considerably. Similarly, within the middle of our brain are fluid filled cavities called ventricles and these become very much enlarged. The other thing that we see and how we identify someone is actually having Alzheimer's disease is they develop two, what we call patho pneumonic or disease hallmarks. One of them is intra neuronal tangles. This is an example of a tangle here. And the other thing is extracellular or extra neuronal plaques. And you may have heard of this term and sometimes people call them neurotic plaques or senile plaques. This is an example of a plaque. These are in the parenchyma or they're extracellular whereas the tangles, the other feature of the disease are actually within the neurons until the neurons actually die. Now, once these tangles form in neurons over a period of time, eventually the neuron dies and we are left with just the tangle. And the tangle remains in the brain because it is an insoluble buildup of protein and even the natural phagocytic cells in the brain just aren't able to eat it up and remove it. So when the neurons die, they cannot be replaced. Neuronal loss as you might be aware is permanent. And because it's permanent, by the time the disease reaches this tangled stage and the neurons are starting to be lost, even if we were able to intercept the disease at that stage, we would still leave the person with a permanent disability or their symptoms could not. So the thing that we really need to get is pre-symptomatic treatments. We need to work out what is the earliest problems that this disease causes on the neurons and try and stop the neurons from dying in the first place. On the right-hand side here, we have a sort of graph which gives you an idea of this prodrone or pre-symptomatic period that I talked about. So there is the disease and particularly something called amyloid beta accumulation. Amyloid beta is what makes up these plaques. This is happening probably up to around about 30 years before the disease actually shows symptoms. And when the disease shows symptoms, we have one stage called mild cognitive impairment and then people go on to be more severely affected and that's when they start developing dementia. So we have certain both imaging and also blood biomarkers that we can look at and get a fair idea that someone might go on and develop dementia. What we then need to find is a treatment target where we can tie the person in this pre-clinical phase. So that we can maintain their cognitive function and this is what we refer to as pre-symptomatic treatments. So what do we know about Alzheimer's disease and what do we think happens at the moment? In 1992 and then again this has been updated, probably updated almost every 10 years but first updated in 2002 was this amyloid cascade hypothesis. And what this proposes is that amyloid and amyloid is produced as a proteolytic or protein degradation product of a protein called APP. Now for some reason this amyloid, excuse me, for some reason the ABTA which we use the abbreviation AB here wants to stick to itself and it starts forming firstly oligomers. And then those oligomers form five fibrils and those fibrils ultimately turn into these neurotic plaques and become quite toxic to the cells. And particularly the neurons and it's thought through a number of processes although these are all to some extent debatable. You get the tangle formation which is a tangle down here and eventually that tangle formation ends up in strangling the neurons and leading to their death and that's how we get the symptoms. So this is still the main idea of how Alzheimer's disease works. However, since around about, just after the turn of the millennium and then more so from around about 2010 there have been a number of treatments that have been used in clinical trials to try to remove amyloid. And they have successfully removed amyloid, these drugs we call an ABTA modified drugs. But the problem is when they've looked at the imaging, yes, the amyloid which is shown in yellow and particularly in red here moves away from these patients but there is no change in their cognitive decline. And this has been a real problem for the amyloid cascade hypothesis. Now you may have heard on the news that a company called Biogen very recently actually got approved to use one of these ABTA modifying drugs called Etihil, also known as a eju-canimab by the FDA. Now FDA is the American equivalent of our TGA here in Australia. And there's a lot of people who felt that this was a rash or overly rushed decision. At the moment Etihil is not available in Australia and even then they think it's only going to be useful in the early stages of the disease. So whether Etihil can help by reducing the amyloid remains very, very contentious. So what it's meant is that researchers like myself have looked in other way, other areas, including the buildup of tau to try to find other processes that might serve as a suitable target for these pre-symptomatic treatments. One of the ones that we're spending a lot of our time looking at is this development of inflammation. There are two types of cells in the human brain. One is called microglia and the other is called astrocytes. And both these cells can become involved in inflammatory processes. And we think that if we can manipulate those inflammatory processes, then we are in a good position to try to slow or even stop Alzheimer's disease. Typically with any disease, the real workhorses of medical research and we can call this pre-clinical medical research or sometimes called basic science, mice and rats. That is because they are mammalian species. They have all the other same organs as what we do as humans. But one issue with using mice as model systems is that their brain relative to say their heart or their guts or any other particular organ is quite different to the human brain. And what a lot of people have found is that they have been able to cure models of Alzheimer's disease and these mice. But when they bring drugs into from these pre-clinical studies into clinical trials, they are often unsuccessful and almost everyone is unsuccessful in clinical trials. And so many of the larger drug companies in the world you recognize fires are here with their recent COVID vaccines that actually stopped in your own science programs. And what we believe at the University of Sydney and in my lab is that there is another way of trying to model this disease. And it might seem a little bit odd, but we suggest that we can actually use donated brains for Alzheimer's disease research. And I wanted to lastly talk a little bit about how we think that this can be done because it does seem given a post-mortem brain tissue is inherently retrospective. It would be very difficult to find early clues to the disease. But what we think is possible was that when AD develops in an individual, it starts in areas such as the hippocampus, which is very deep in the brain and is actually very old evolutionary old part of the human brain and then tends to move out from there. So at post-mortem, there are areas of the brain that are relatively unaffected by the disease. And we think that some of these areas could be used as a proxy for those severely affected areas 20 or 30 years earlier in the disease course. And so almost by reversing the disease course, we can use these particular areas to say, hey, maybe these have the same processes going on as what would have been happening in the hippocampus 30 years earlier. IE we can use these belatedly affected areas at all top C of the AD brain as proxies for areas like the hippocampus many, many, many years earlier. Now, using this model, our research goes on to do two particular things. And I've called it sort of a brain of two halves. And that's because when we get a brain donated, we divide the brain in half and one half of it is fixed. And we use that to look at the structure of the brain we call these type of studies, immunohistochemistry. And then the other half of the brain is frozen. So it's cut up into what we call blocks and then those blocks are frozen down. And that allows us to do molecular studies. And it's by combining information that we get spatially with information that we get molecularly that we think that the areas like that I pointed to earlier. In some cases, one area would be the primary visual cortex. For example, we can use those areas in these combination of techniques to work out what's happening early on in Alzheimer's disease. I have been recently working with a fantastic group at the University of Washington in St. Louis over in America. And they have been using a very new technique called single cell RNA sequencing to work out what all the cells in an area of the brain. And when I talk about all the cells, I'll mention close to 100,000 different cells where all of those cells are expressing. Now, as you might imagine, that type of molecular analysis gives us a massive amount of data. And particularly when we do it over a large number of brains from both people with the disease and those people without. The data is extremely complex and very, very dense. So what my lab does, and this is some work that a former student of my Julia Lim does, is to go through these areas of the brain on the fixed side and quantify the amount of tau, the amount of amyloid in those areas, and also the amount of neurons that are left. And therefore, we were able to divide that very complex data that I referred to just previously. We can divide it up into not only pathways that are different between people with the disease or not, but we can also divide them up into pathways that seem to be tau-related, amyloid-related, or maybe unrelated to those two hallmark pathologies that I spoke about earlier. The plaques that are made up of amyloid beta and the tingles that are made up of tau. And so again, by combining these two halves of the information gain from these two halves of the brain, that's how we go about digging into this complex data to find these potential therapeutic targets in Alzheimer's disease. And then once those are put together, we use the term sort of a mirror atlas of AD. Here is a chart of basically showing you exactly what we do, summarizing what I just said. So on a fixed part of the brain, we use very sophisticated microscopy to take lots of images of those particular brain areas, and we quantify all the pathology and all the cells that are in that area. And then from the opposite side of the brain, we get dense molecular data. And then we use what we know about the spatial brain and how many different types of cells there are to make more sense of this very complex and dense data that we're now able to generate with our biological studies. And just lastly, as I've seen, we've used two sides of the brain up to this point. But on the horizon is a technique called spatial transcriptomics where we can actually do the both experiments, the molecular and the spatial at the exact same time on the same side of the brain. And that's a very important thing. It means we are only doing one type of the experiment. And we think that this is going to be the future of our work where we can relate in one go some very complex information about what abnormal cells in an AD brain are expressing and how other cells are relating to that as at the same time of capturing those cells in situ. And I think this is going to be a major step forward towards realising our goal of finding those pre-symptomatic therapeutic targets. Of course, it would be a miss of me not to mention the most important people in this story. And that is the patients. 10 years ago, also, I lost a very dear friend who'd been a mentor of mine, a fellow veterinary surgeon called John. John, like many people without Simon's disease, had the disease over 10 years and slowly lost his cognitive abilities. It's a very sad process, but he put up a great fight and he was a lovely old man. Just in the background, the hoist, people with this disease in the last few years of it are immobile and have to be moved around during sleeping and also moved around their house. And it's a great imposition on caregivers and often those caregivers are a direct member of the family. In John's case, it was his wife. And so there is a lot of indirect effects of Alzheimer's disease as well as on the patients themselves. And lastly, just a few of my colleagues and collaborators would work with people all around the world. It looks like a very busy page and it is. But importantly, I just want again to thank the patients and those patients who make the very kind decision to donate their brain after their lives and, of course, the next that can allow that process to happen. Thank you very much. If you have any interest in Alzheimer's disease or anything that I've talked about today, please don't hesitate to contact me with the University of Sydney, g.sutherland at Sydney.edu.au.