 Good afternoon, everyone. It's a pleasure to talk to you today about risk assessment to advance brain health and dementia prevention. So I'm going to start off our talk with a few stats, and I hope this slide's not too heavy for everybody. But I wanted to point out in those figures on the left of the slide that dementia in late life, this is in people over the age of 60, increases quite dramatically with age. So every five years approximately it doubles. And it becomes really highly prevalent in people over 80. So people in their 80s and 90s make up the bulk of the group of people who have late life dementia. And what's important here is that overall we don't see, in the meta-analyses, when you sort of merge all the data globally, we don't see sex differences. But when we look at Alzheimer's disease, we find that is more prevalent in women than men. So we do see more dementia in the over 90s in women, and that's because women live longer than men. But apart from that averaging everything out, it's roughly the same except for Alzheimer's disease. There are particular population groups and demographics where we see higher rates of dementia. And that's often related to different risk profiles. And in Australia we have very high rates of dementia in the studies that have been conducted on First Nations Australians. So approximately three times the expected rate of dementia. And we think that is probably due to a different risk profile. I mean there's been a number of areas of disadvantage that compound to impact brain health. Lower rates of education, poorer control of metabolic disorders and diabetes and so forth. And high rates of head trauma. The distribution of the types of dementia that we see in First Nations peoples is fairly similar to what you see in all of the other studies. So it's still Alzheimer's disease is the most prevalent cause of dementia in nearly all populations except possibly some countries in Asia where some literature has suggested that vascular dementia is more prevalent. So I just want to talk to you about the risk factors for dementia. We have both non-modifiable risk factors and modifiable risk factors that we can look at in our research. And in the non-modifiable risk factors it's mostly things like the country you're born in, genetics, sex at birth, ethnicity and so forth. And then the modifiable risk factors we divide into two categories. There's the ones that occur at the individual level. So things like your actual, your BMI, whether or not you're physically active and live in a healthy lifestyle. And then there's factors that we think occur at the policy or social level and they may be the social determinants of health, things like air pollution as well and education levels. I'm just going to talk very briefly about genetics and then I'm going to move on to modifiable risk factors after this slide. So first of all, there is one main genetic risk factor for dementia and that's a risk factor specifically for Alzheimer's disease. It's called the apolipoprotein E4LL. It's actually really common. So people often don't realise that one in four of us carry this and that increases your risk of Alzheimer's disease by three times. That's late life Alzheimer's. We're talking about not Alzheimer's in younger adults. If you have two copies, it increases your risk by five to eight times. Now, what's really interesting though is that this is neither necessary nor sufficient for you to develop Alzheimer's disease. In our cohort study we run, we've been running for over 20 years called the Path Through Life Project. We've got people in that study who are homozygous, things that have two copies of the E4LL and they're not declining cognitively. They're actually quite resilient. So there's a number of other things that are going on and so this has led researchers to put a lot of energy into looking at what is causing neurodegeneration and dementia in addition to the genetic risk factors and those non-modifiable risk factors. So the rest of my talk is actually going to focus on the modifiable risk factors. So first of all, what happens if you have the genetic risk factor? I mean how important is lifestyle? Can you still do something? The answer is yes. So we've looked at this in the Australian data in our Path Through Life cohort and we found that the genetic risk for Alzheimer's disease was independent of lifestyle and medical risk factors. And in this big study which is shown on the slide here was a meta-analysis where they reviewed the literature to look at lifestyle factors versus genetic risk for Alzheimer's. They again found that they're independent. They're both significant predictors of Alzheimer's disease but they had an independent contribution. And people who had the genetic risk, who had a healthier lifestyle, that reduced their overall risk. So it was still beneficial to undertake lifestyle change even if you have the genetic risk. So how much, you know, the next question might be how much can you modify your risk of dementia? Well at the individual level for one particular person it's impossible to say if you do everything, all of these things you will not develop dementia or Alzheimer's disease or vascular dementia. It's a bit like smoking and lung cancer where some people develop lung cancer and they've never smoked. But we know at the population level on average if everybody adopted healthy lifestyle and treated their medical conditions and we could address social determinants of health we could make a big impact on dementia. So the Lancet Commission in 2020 conducted a big data synthesis and did a lot of statistical modelling to try to work out how much of dementia could be attributable to some of the key risk factors. And they concluded that about 40% of dementia globally is attributable to modifiable risk factors, which is actually quite a big amount. And then individual countries and researchers, you know, they've looked at the population attributable risk in their country or in their population subgroup within a country. And often they've found an even higher proportion of cases of dementia could be attributable to modifiable risk factors. So the risk factors that the Lancet Commission focus on, there's 12, they're shown on the slide and I'm just going to run through them. They take a life course approach so they argue that in early life low education is a significant risk factor. Now if you look at that slide it says the risk factor prevalence is 40%. Now that's because globally low education is quite prevalent. So 40% of the world's population whereas in Australia low levels of education. So not say just finishing a primary school not going beyond that. It's actually quite much lower. So we don't have, you know, this obviously we have a different pattern of risk exposure in Australia. We have higher rates of some of the risk factors though. In middle age the risk factors identified by the Lancet Commission included hearing loss, traumatic brain injury, hypertension, alcohol, heavy alcohol consumption. So more than three drinks a day. Obesity in middle age, they're all in midlife. And in late life they've identified smoking, depression, social isolation, physical inactivity, diabetes and air pollution. Now this is in a really important list but it's not the only authority on these risk factors. There has been a lot of work done even since 2020 on risk factors for brain health and dementia. And there are also some other sources of information. So there's actually quite a few more risk factors that are included on this slide. So for example the World Health Organization published its guidelines on risk reduction for cognitive decline and dementia in 2019. And it included high cholesterol in midlife and makes recommendations about management of high cholesterol. And since then and since the Lancet Commission there's been more systematic reviews published on high cholesterol. And it seems quite conclusive that high cholesterol in middle age is a risk factor and should be treated. The other really important risk factor which is not included in the Lancet Commission report here but we think is very important. There's a lot of evidence for it and that's a poor diet. So there's really been a lot of research looking at dietary patterns and just brain health generally. So in populations we're not looking at people who've been diagnosed necessarily with any neurological condition. If we just look at a population study, most studies are finding an association between healthier diet and less cognitive decline longitudinally. So we see that over and over again and we see in the meta-analysis a protective effect of the mind diet. And particularly the type of mind diet that's emphasises neuro-protective properties which includes green leafy vegetables every day and blueberries. I wanted to talk a bit about the medical risk factors. So we talk a lot about lifestyle and I think there's probably less known about some of the medical risk factors for Alzheimer's disease and dementia. Now this information is mostly taken from observational studies so the diagnosis of those outcomes is not high tech. They don't have usually pet imaging, they don't have blood biomarkers, it's a clinical diagnosis. And there's often a lot of mixed dementia in these studies and often the outcome is just all cause dementia. And these are studies where they follow people into old age. So we're talking mostly about factors that have been shown to impact late life dementia. And of course some of these risk factors are also linked to brain health generally and to neurological conditions at younger ages. Now the medical conditions, the main ones are diabetes, heart disease, depression, stroke, kidney disease, hypertension in middle age specifically not in late life, obesity in middle age, not in late life, head injury and then there's quite a bit of research looking at medications and whether or not they're protective. That's almost like a whole talk in itself and then there's also been looking at some infections as well. I'm just going to look at a few of these medical risk factors, we don't have time to go into all of them but I thought I'd just show you some of the findings on some of the key ones. So diabetes has been very well studied and the findings in relation to diabetes are fairly robust. Mostly they show that people with type 2 diabetes have an increased risk of cognitive decline and are more likely to experience decline in executive function to develop cognitive impairment and dementia. But the effect is more for vascular dementia than Alzheimer's disease and actually a number of the autopsy studies don't find any more Alzheimer's pathology in people with diabetes than without. So it really seems to be the vascular changes that occur with diabetes that's increasing the risk. Now if you move to heart disease, most types of heart disease have been associated with an increased risk of all cause dementia in late life. In particular atrial fibrillation has been shown in a number of systematic reviews to increase the risk. But other studies have found associations with more general heart disease, heart failure and so forth. Blood pressure is something that, high blood pressure is very common, we all have our blood pressure tested every time we go to the GP or regularly. And high blood pressure in midlife has been associated with an increased risk of cognitive decline and dementia. The thing is it's been difficult to find the association with Alzheimer's disease and most of the effect has been with vascular dementia and it's mostly been in middle aged people. It's less clear how hypertension affects the brain in later lives and that is an area of ongoing research. I've seen very, very recent work looking at things like changes in blood pressure, variability in blood pressure. But we know definitely that high blood pressure in middle age is a significant risk. The good news is that treating high blood pressure does reduce that risk and it doesn't seem to matter which type of medication is used. And people who have hypertension who are then treated with antihypertensives and bring their blood pressure down, that does seem to reduce their risk. Now obesity is another quite an interesting risk factor because it's middle aged obesity that seems to increase the risk of late life dementia specifically. But when people are overweight in later life, so 65 and older, that doesn't seem to be associated with an increased risk. So we don't understand the mechanism underpinning the association. There's a number of theories that it has been observed over and over again. And another medical respect which I think is not widely understood or known about often is depression. So depression has been linked to an increased risk of late life dementia. And initially this was thought to be what we call reverse causation. So it was thought that it was noticed that as people start to have cognitive difficulties in their daily life, they often withdraw and their mood is affected. And there's some common causal pathways underpinning mood and affect and mood disorders and cognitive decline. So it was thought that the link between the two was really it was all just caused by a single process. And that it wasn't that depression was causing it was causally related to cognitive decline. Since then there have been a lot of long term studies where they've been able to look at people who were depressed way before they would show cognitive decline. So middle aged adults and they have shown that people who have a history of major depression do have a long term increased risk of dementia in late life. So I'm just going to really talk briefly about the lifestyle and environmental risk factors because we've spent more time on the medical risk factors today. The lifestyle risk factors cover things like diet, physical activity, smoking, heavy alcohol consumption, sleep, cognitive engagement, social engagement. And the environmental risk factors, air pollution is a well established risk factor for cognitive decline. And then there's a lot of emerging evidence in a number of areas which I think in a couple of years will understand a lot more. But there's a lot of research looking at things like your exposure to green space, walkability, blue space, occupational complexity, noise and so forth. I just wanted to quickly mention alcohol because it always comes up in questions and I think most people want to know what's good for their brain health with respect to alcohol. And the message can get a bit confusing with alcohol. When we've looked at our observational data, so we've followed people over many, many years, what we see and we've seen it in our Australian cohort and we see it in the reviews of cohorts when we're looking at multiple cohorts together, is that people who have a light level of alcohol consumption tend to have better brain health and reduce risk of dementia. Usually up to one or maybe two drinks a day. However, there's a number of ways of looking at this whole issue of alcohol. One is that any alcohol consumption has been shown to increase some types of cancer risk. So you can't just look at alcohol and cognitive outcomes or brain health in isolation from general health. In fact, the World Health Organization says there's no safe level of alcohol consumption. And some people argue that the people who aren't drinking, so the comparison group in our research, may in fact have been former drinkers or have serious medical problems that meant their cognition or their risk of dementia was greater. So we may not be actually comparing the light. The light drinkers may not be being compared to the correct comparison group. It's one of these conundrums where we can't ever really determine it without a randomized controlled trial and it's probably unethical to conduct such a randomized controlled trial. So then people have looked at mechanisms, biological mechanisms, neuroimaging to try to unpick and unravel what's going on with alcohol. Now there is evidence that heavy drinking, particularly in middle age, so more than three drinks a day, seven days a week in middle age, does increase your risk of late life dementia. And this was reported in the Lancet Commission 2020 and that's why the Lancet Commission includes alcohol in its list of midlife risk factors. There's now emerging evidence on sleep, so the whole question of sleep and cognition and brain health is very complex. Again, because of that direction issue, we don't know which way the directions go. Is poor sleep a result of having a neurological problem or some preclinical dementia? After a lot of work and it's still very much an active research space, but at the moment the consensus is that sleep apnea appears to increase the risk of dementia when it's untreated. So it seems that people with sleep apnea have a 34% increased risk of developing all cause dementia and 54% increased risk of developing Parkinson's disease compared to people who don't have those disorders and when their sleep apnea is untreated. Now an important fact about all of this risk factor information, so by now I'm sure everybody's identified many risk factors that they have or their friends have or their family have because there's so many risk factors that almost everybody has some. They are cumulative, so the more risk factors you have, the greater risk of dementia, your greater risk of dementia. So they do accumulate and that's why when we look at trying to improve brain health and reduce risk of dementia, we want to take an approach that addresses multiple risk factors at once. And we need a reliable way to assess risk, otherwise we can't implement risk reduction policies and clinical practice guidelines. So risk assessment is really essential, accurate risk assessment for dementia is important for GPs, for people themselves to be able to assess their own risk. And also we use some risk assessment in our population modelling to give guidance to government around a public policy. So we developed an evidence-based reliable method of assessing risk factors for dementia and it's called Cogdea Risk. It's freely available on the Neuro website, I've got the URL here on the slide. This was developed through sifting through the literature over five years and synthesising all of the risk, the weights, the relative risks of all of the key risk factors. And once we developed the algorithm for this, we validated it on for international high quality cohort studies. We've also developed a short form and a Chinese version of the Cogdea Risk. The Cogdea Risk has a number of domains, so you complete the questionnaire and then you get feedback about and you can choose feedback in whichever order on your health, your sleep, your food and habits, etc. Once you've completed it, the program will generate a report for you telling you areas where you're going well and areas where there's room for improvement. And you can take this report to your GP and discuss it with them or you can follow the advice. The advice given here is all evidence-based, it's all based on things like the National Health and Medical Research Council guidelines or the WHO guidelines. Just out of interest, I thought I'd show you the relative weights of the risk factors that we have in the Cogdea Risk. What's interesting here is the cost of low education less than eight years is the biggest risk factor, has the biggest weight. But actually depression comes up fairly high as having one of the highest risks, increasing the risk of dementia and the vascular risk factors. So risk reduction obviously for all of us personally is very beneficial, enables us to take control and do what we can. And even if you have a neurological condition or you have dementia now, there are benefits for you to reduce your risk or if you've got MCI, all of these things promote brain health as well as reduce your risk of dementia. But there's also the economic benefits of risk reduction and have been some economic studies done. So there's been simulation studies and cost-effectiveness analyses. I won't go into the details here. But they've basically all shown that there's quite a big economic benefit for us to implement risk reduction. And for example, an intervention that could delay the onset of Alzheimer's by five years could result in 41% reduced prevalence of Alzheimer's in the population and a 40% lowering of costs. That was simulation work. And then other work from the trials has shown an enormous benefit through risk reduction in preventing future cases. So just to summarize, late life dementia is highly prevalent in the population, increases with age. There are a number of newer developments which I haven't discussed today. And there's both genetic and lifestyle risk factors. But the important message is there's a lot of modifiable risk factors for brain health and for dementia. And we can make quite a significant impact through risk reduction. Those risk factors seem to have an additive effect. So we tend to recommend addressing multiple risk factors if you have them. And this approach is cost-effective. And it has many benefits for you personally and for society. Basically promoting healthy aging, generally, not just brain health. And that's all. Thank you.