Professor Kaarin Anstey
In epidemiology we look at a particular health problem in terms of the population. Whereas clinicians are just focusing on an individual patient, in epidemiology we want to look at the prevalence, so how common is a particular health condition across the entire population, and at what rate does it increase. So we talk about incidence. So if we’re looking at dementia, we’d say, “how many people have dementia at this point in time?” - that’s the “prevalence.” And “over the next five years, how many people would develop dementia?” - that’s the “incidence.” And then another critical aspect of epidemiology for this is looking at “risk factors,” so things that increase the chance that a person will develop the disease that we’re studying.
在流行病学的研究中,我们是从人群水平来了解某一特定的健康问题。临床医生只是专注于个体患者，而在流行病学中，我们是要观察患病率，即在整个人群中特定的健康问题有多严重。另外还要观察它以什么样的速度在增加，所以我们谈论发病率。因此当我们研究认知症的流行病学时，我们会说，“在这个特定时间点有多少认知症患者？” - 这是指“患病率”。而“在接下来的五年中，会有多少人发展成认知症？ - 这是指“发病率”。此外流行病学的另一个关键点是观察“风险因素”，就是增加一个人发展我们正在研究的这种疾病的概率。
I’m going to be talking about the types of epidemiology studies that are conducted, to answer questions of prevalence, incidence and risk. So, to get the prevalence of a disease, say dementia, we need to have a sample that we study that is representative of the population. Ideally, for example, in Australia we would take a random sample of the entire population of Australia, but we’ve got such a large land mass here that’s not possible. So we often do a representative sample of a particular region, and then we extrapolate up to the country population from that. So that’s a single, one-off survey that we could do or study. Often we want to do a longitudinal study, especially if we’re looking at risk factors. So we take a cohort and we do a longitudinal study or what’s also called a prospective study, or it’s sometimes called a cohort study. And that’s where we take this group of people who’ve been sampled randomly from a defined area or population, and we follow them over time, and we test the same people again and again and again. And we look at how their risk factors may change and whether or not they develop dementia longitudinally.
How useful is an observational study or an epidemiology study in the field of dementia epidemiology in establishing a risk and causality, compared to a randomised control trial? To answer that question, we actually have to take a step back. And we have to think about the fact that dementia occurs due to pathological changes in the brain, and these occur over decades. So they’re not occurring over a very short period of time like 12 months or two years. And, so, we can’t actually conduct short-term studies on the causes of dementia at the population level; we need to have that long-term information to see who’s going to go and develop dementia. From that point of view, we’re really left with cohort studies as the main method of studying risk for dementia.
And, secondly, a number of the risk factors that have come out from the research that’s been conducted are things that we couldn’t examine using a randomised control trial methodology. I’d just better explain what a randomised control trial is. A randomised control trial is when you take a sample and you randomly allocate the members of the study to different conditions, and then because of the randomisation, you’re able to adjust for all of the potential factors that may influence the results. So, for example, you might conduct a randomised control trial of a drug that theoretically is thought to prevent dementia, and every person who came in would get a random allocation to drug, or no drug. The problem is, with dementia, again, it takes so long to develop and the brain changes take a long while to accumulate, so we couldn’t conduct a short-term randomised control trial. And, secondly, it wouldn’t be ethical to look at some of the risk factors for dementia in a randomised control trial. For example, we couldn’t ask people to smoke to see if smoking caused dementia. We couldn’t expose people to heavy air pollution, to see if that causes brain damage that’s irreversible. The sort of questions that you’d end up asking are just almost illogical and they’re completely unethical. So we really can only look at these questions using what we call observational studies, where we look at exposure just through normal life, whether the people chose to smoke, whether they lived in an area with heavy air pollution, and then we use statistical methods to try to adjust for all of those potentially confounding factors. And then we follow people up and see if those what we call “exposures,” so exposure to smoking or air pollution or heart disease of whatever, if those things increased the risk long-term of dementia.
So, the question is: how do we evaluate the results of observational studies that show, for example, factor A is a risk factor, and then a similar study in another country might find it’s not a risk factor? There’s a number of approaches to this problem. This is something that we deal with – well, I in particular in my group, at the Australian National University, deal with a lot. First of all, we look at the quality of the research design of the study that found the result, did they adequately adjust for potential confounders? Was the sample biased? How long did they follow up the sample; is it a long enough follow up? Was there a lot of sample attrition leading to sample bias? Were the measures adequate? Did they properly measure the exposure and did they have a proper measure of dementia diagnosis at outcome? So you look at all of these design issues. Was it a big enough sample to give a statistically robust result?
So that’s the first approach, and sometimes that alone will tell you that the result is probably not reliable, because there are methodological flaws in the study or limitations that mean it’s inconclusive. Secondly, what we do in this field of dementia epidemiology is that we consider each cohort study as one study in a sample of studies, and there’s actually a population of these studies, so we assume there is a true finding of an effect. So we do something called “meta-analysis,” and that’s where we bring together all of the different studies on a particular topic. So if we took, for example, smoking, does smoking increase risk of dementia, we would get all of the published studies on smoking and risk of dementia and we’d use statistical methods to pool the results. And that gives us a robust estimate and we can actually look at something called the study bias, the selection or publication bias using statistical techniques to see if we have got a good representation of all of those studies. And, from that, we derive a much more robust estimate of the effect and a standard error around that estimate, and that’s really what we prefer to use, rather than just the result of a single study.
丁宇欣 Yuxin Ding
锦州医科大学高级护理专业、注册护士、中国人民大学公共管理学院进修2年。英国阿尔茨海默症协会Dementia Friends认证的认知症好朋友、获得澳洲塔斯马尼亚大学Wicking认知症研究中心Preventing Dementia课程证书和UnderstandingDementia课程证书。
Dr Maree Farrow
Often we see headlines in the media that might tell us a certain behaviour will increase our risk of dementia while another behaviour might reduce our risk of dementia. Those headlines, unfortunately, can be misleading. They can leave us believing that we could eliminate our risk of dementia completely simply by eating more chocolate or drinking more coffee. But what do those headlines really mean?
Let’s talk about how researchers actually find out how a particular behaviour affects our risk of developing dementia. Let’s say we wanted to find out how eating cheese is related to the risk of dementia. Now it’s not, as far as we know. There’s been no studies looking at this, so please don’t worry about eating cheese. This is a hypothetical example that we’re going to use here.
One of the best ways to look at this question would be to conduct what we call a prospective cohort study. In this type of study, we’d recruit a random sample of people and we’d ask them how much cheese they eat. Then we’d follow them up over a number of years to determine who gets dementia, and whether how much cheese they eat was related to their risk of developing dementia. Then we would use statistics to determine whether eating cheese had a significant effect on your risk of developing dementia and also how big that effect might be.
In our hypothetical research study, we’re going to start by recruiting two thousand people who are aged over 65. We’re going to ask them how much cheese they eat and we’re going to split them into two groups. We’re going to take the people who eat more than 100 grams of cheese per week and then the people who eat less than that amount per week. So in this hypothetical study, let’s say we were able to split the group in half. So we have one thousand people who eat more than 100 grams of cheese per week. We’re going to call them the high cheese group. Then we have another one thousand people who eat less than 100 grams of cheese per week, and we’re going to call them the low cheese group.
To do this study well, we’d need to match our two groups on things like age and gender, the other things that they eat in their diet, and any other factors that might affect dementia risk, so that how much cheese they ate was the only thing that was different about the two groups. We would also test their cognitive function at the beginning of the study, to make sure that they didn’t have dementia at the start. After this baseline testing, we’ll follow our two thousand participants for the next ten years, and we’ll meet with them every two years to test their cognitive function, and in that way we can determine if anyone develops dementia over that time.
So in our hypothetical study, let’s say we found that over the ten years 120 people developed dementia. Now 80 of those were from the high cheese group, so that represents 8% of the people in that group who did develop dementia over those ten years.
In the low cheese group, however, there were only 40 people who developed dementia, so that represents 4% of the low cheese group.
And we might start to think about whether eating cheese is such a good idea. But what do these numbers really mean? There’s two different ways we can look at the findings - depending on whether we’re interested in the effects of eating a lot of cheese or the effects of eating not much cheese.
另外我们可以开始考虑吃奶酪是否是一个好主意。但这些数字真正的含义是什么呢？我们可以有两种不同的方式来看结果 - 取决于我们是否对吃大量的奶酪或吃不太多的奶酪的影响感兴趣。
Let’s first look at how eating high amounts of cheese affects dementia risk in our hypothetical study. From our finding that 8% of people in the high cheese group developed dementia compared to 4% in the low cheese group, we can conclude that eating high amounts of cheese might double the risk of developing dementia. We could also say that eating high amounts of cheese increases the risk of dementia by 100%. Then, as researchers, we would calculate what we call a risk ratio, and in this case the risk ratio is simply eight divided by four, which is two.
A risk ratio of two means exactly the same thing as increasing the risk of dementia by 100% or doubling the risk through eating high amounts of cheese.
We would then use statistics to determine if our risk ratio is significant. A statistically significant risk ratio means that we can be reasonably certain there’s a real relationship between eating cheese and the risk of developing dementia, rather than it just being due to chance.
To investigate the effects of eating small amounts of cheese, we would look at our results the other way around. From our results that 4% of people in the low cheese group developed dementia, compared to 8% in the high cheese group, we could conclude that eating small amounts of cheese halves the risk of developing dementia, or that the risk is reduced by 50%. And the risk ratio in this case would be four divided by eight or 0.5. So again having a risk ratio of 0.5 is exactly the same as halving the risk or reducing the risk by 50%. And once again we would need to use statistics to determine if that relationship was statistically significant.
Doubling your risk of dementia sounds pretty scary, while halving your risk of dementia sounds like a good idea. So would you give up eating cheese based on these findings? There are some very important points to remember when looking at research findings like this.
Firstly, although the relative risk of developing dementia was doubled by eating high amounts of cheese in our hypothetical study, the absolute risk changed by only a small amount from 4% to 8%. The other 92% of people in the high cheese group did not develop dementia, despite the fact that they consumed those higher amounts of cheese.
Secondly, a finding like this does not mean that eating cheese causes dementia. What we found was an association between the two things, but this does not represent a causal link.
And finally, a study like this can’t tell us everything about the relationship between eating cheese and developing dementia. What about younger people? If they ate lots of cheese would that affect their risk of developing dementia later in life? What about the type of cheese you eat? Is parmesan cheese better or worse than gorgonzola? And what about the amount of cheese you eat? If 100 grams of cheese per week increases the risk, would 200 grams of cheese per week increase the risk even further?
What this finding means is that older people who eat more of any kind of cheese might have a slightly higher chance of developing dementia. Don’t forget though, this is a hypothetical question. So if I did eat lots of cheese, based on these findings, I might think about cutting back to reduce my risk of dementia, but I would do so knowing that it wouldn’t stop me getting dementia, and I’d also know that it was only one of many choices I could make to potentially reduce my risk of dementia.
Now what would the media make of these findings? We might see headlines such as “Don’t eat cheese if you don’t want dementia”. But we need to look at the research and the real findings behind these headlines to understand how relevant they are to us.
Here’s an example of some real newspaper headlines from a few years ago. Firstly, “Coffee – just the shot to fend off Alzheimer’s.” And “Caffeine addicts rejoice – a cup a day may keep Alzheimer’s at bay.” You might expect the research was conducted in a similar way to our hypothetical cheese study. A human prospective cohort study investigating the link between coffee consumption and the risk of developing Alzheimer’s Disease.
“咖啡 - 只是防止阿尔茨海默病的镜头”和“咖啡因成瘾者喜出望外 - 一天一杯可能会远离阿尔茨海默病”，这是几年前某些真正报纸头条的一个例子。首先，你可能希望以类似前面我们假设的奶酪研究的方式进行一项人类前瞻性队列研究来调查喝咖啡和发展阿尔茨海默病的风险之间的联系。
However, here’s the title of the article published by the researchers in the Journal of Neuroinflammation in 2008. “Caffeine blocks disruption of the blood brain barrier in a rabbit model of Alzheimer’s Disease”. The participants in this particular study were rabbits fed a high cholesterol diet.
The researchers tested whether chronic ingestion of caffeine in their rabbits could protect them against changes in the blood brain barrier brought about by their high cholesterol diet. High cholesterol diets and high cholesterol levels, as well as disruptions in the blood brain barrier, have been associated with Alzheimer’s Disease, and also there have been studies suggesting that coffee consumption might be protective against Alzheimer’s Disease. So this is a reasonable research question.
The researchers found that in their rabbits, caffeine consumption blocked the usual changes in the blood brain barrier brought about by their cholesterol-rich diet. And the researchers concluded that caffeine, and drugs similar to caffeine, might be effective in the treatment of Alzheimer’s Disease.
Now it’s rather a long stretch to go from that research to suggesting that humans could fend off Alzheimer’s Disease by drinking more coffee.
The participants in the study were rabbits, not humans. They didn’t have Alzheimer’s Disease. They were fed a cholesterol-rich diet as a potential model for Alzheimer’s Disease. They didn’t drink coffee, they were given pure caffeine in their drinking water. Also, the researchers suggested that caffeine could potentially be used as a treatment for Alzheimer’s Disease, not as something that would prevent Alzheimer’s Disease.
So be wary about making decisions based on media headlines. They may not accurately reflect the research that they’re based on. And also remember the difference between relative risk and absolute risk. A doubling in the relative risk of developing dementia might be something we should take notice of. But it may mean just a small increase in the absolute risk of developing dementia.
Hello and welcome to the Wicking Dementia Laboratory, where one of the things we are working to understand is the genetics of dementia. When someone in their family has dementia, people are naturally concerned about whether it can be inherited. The genetics of dementia is complex and not fully understood. However, we do know that the vast majority of cases of dementia is not caused by an inherited genetic mutation. Dementia is so common that having several close relatives with dementia is not evidence of a genetic link.
There are a few gene mutations we know about that do cause dementia, however. So for a very small number of families, dementia can be inherited when the mutation is passed on. In these rare genetic forms of dementia, the onset is usually at a younger age, in the 40s or 50s.
Let’s meet one of those families. This is the Appleton family.
This is Alan Appleton, and he has familial Alzheimer’s disease. He inherited a faulty gene that causes Alzheimer’s from his mother, who also had the disease.
Three genes have been identified which, if mutated in certain ways, will cause familial Alzheimer’s disease. The mutation causing Alan’s Alzheimer’s is in a gene called APP.
We inherit half our genes from our mother and half from our father. While Alan inherited a faulty copy of the APP gene from his mother, he also inherited a normal copy from his father.
This is Alice, Alan’s partner. Her mother also had Alzheimer’s disease, but it was the common sporadic type, so Alice has two normal copies of the APP gene.
Meet April and Augustus, Allan and Alice’s children. When someone carries a faulty gene that causes dementia, there is a 50-50 chance they will pass it on to their child, because they could pass on either their faulty or normal copy of the gene.
April inherited the normal APP gene from her father and from her mother, so she will not get familial Alzheimer’s disease. She could still get sporadic Alzheimer’s disease, but she is at no greater risk than anyone else in the population.
Augustus on the other hand, inherited the faulty APP gene from his father and a normal gene from his mother. He will develop familial Alzheimer’s disease because the mutated gene is dominant over the normal copy.
Genetic forms of Alzheimer’s disease like the one affecting Alan and Augustus Appleton account for only around 1% of cases. So the vast majority of cases are sporadic, which means their cause is unknown. There are also other gene mutations that can cause other types of dementia, but for all the common causes of dementia, most cases are not inherited.
So what about the sporadic forms of dementia, do genes play a role there? Research shows that, on average, people who have a close relative with a sporadic form of dementia have an increased risk of developing the condition, compared to someone without that family history. The increase in risk is similar to the increase we see for other risk factors like diabetes or smoking. And it is likely due to a combination of genetic and environmental influences on our risk of dementia.
One of the genetic influences on our risk of Alzheimer’s disease is a gene called APOE. This gene comes in three normal variations. APOE3 is the most common variation, and doesn’t influence our risk of Alzheimer’s disease. APOE2 is associated with reduced risk, while APOE4 is known to increase the risk.
对我们患阿尔茨海默病的风险的遗传影响之一是称为APOE的基因。这个基因有三种常见的变异类型。 APOE3是最常见的变异，并不影响我们患阿尔茨海默病的风险。 APOE2与降低的风险相关，而APOE4已知会增加风险。
APOE4 does not cause Alzheimer’s, it only increases the risk of it developing. Some people with APOE4 never develop Alzheimer’s disease, and others who develop Alzheimer’s do not have APOE4. So even if someone has the APOE4 gene, it is impossible to predict whether or not they will develop dementia, but they are at increased risk.
In addition to APOE4, many other genes have been identified that have smaller effects on the risk of dementia. We are each born with an individual mix of genes, some of which may reduce our risk of dementia while others may increase it. At this time, it is not possible to measure any person’s individual genetic risk for dementia.
Thanks for visiting the Wicking Dementia Laboratory and I hope you’ve enjoyed learning about the genetics of dementia.
丁宇欣 Yuxin Ding
锦州医科大学高级护理专业、注册护士、中国人民大学公共管理学院进修2年。英国阿尔茨海默症协会Dementia Friends认证的认知症好朋友、获得澳洲塔斯马尼亚大学Wicking认知症研究中心Preventing Dementia课程证书和UnderstandingDementia课程证书。
Hello. Today in the Wicking Dementia Laboratory we have 12 volunteers who are going to demonstrate the influence of modifiable factors on our risk of developing dementia. There are important non-modifiable risk factors for dementia; things we can’t change. We can’t stop growing older, which is the biggest risk factor for dementia. And we can’t change our family or our genes.
This is a group of 12 friends who have their own individual mix of genes inherited from their parents. Some of them will be at higher risk of developing dementia than others, because of their genes.
We can’t actually measure anyone’s level of genetic risk because it’s complex and involves many different genes. But for the purposes of our demonstration, let’s line up our friends and assume this represents the order of their dementia risk according to the genetic make-up they were born with.
Hypothetically, if genes were the only thing affecting their risk, let’s say 3 out of 4 people in the high risk group would get dementia. 2 out of 4 in the medium risk group would get dementia, and just 1 out of 4 in the low risk group would get dementia.
But genes are not the only factor that affects our risk. Now let’s look at some of the other factors that we know have an effect on our risk of developing dementia and see if anyone’s risk changes.
Let’s start with Brenda, who hypothetically has the highest genetic risk. She eats a healthy diet including lots of vegetables and fruit and fish, which is most likely associated with a reduced risk of dementia, so she gets to move down the line, closer to a lower risk.
Chris uses aluminium pots and pans, but there is no evidence this affects dementia risk, so she stays where she is in the line.
Douglas does regular physical exercise, which is associated with a reduced risk of dementia, so he gets to move down the line, closer to a lower risk.
Edmond smokes cigarettes, and we know smoking increases the risk of dementia, so he has a higher risk and unfortunately he moves up the line.
Fiona is 45 and has high blood pressure, but hasn’t had it checked or treated, and high blood pressure in midlife increases the risk of dementia, so she also moves up the line.
Gary has decided to eat coconut oil every day, but this hasn’t been proven to affect dementia risk, so he stays where he is.
Heidi is learning a second language, and keeping your brain active is associated with lower dementia risk, so she gets to move down the line.
Ivan meets regularly with his walking group and scrabble club. As social activity is associated with reduced dementia risk, he moves down the line.
Joseph is 55 and very overweight, and we know that midlife obesity is associated with increased dementia risk, so he moves up the line toward higher risk.
Katie has diabetes and Luigi has depression. Both can be associated with increased dementia risk if poorly managed, so they move up the line toward higher risk.
Mary has decided to take ginkgo biloba supplements, but there is no evidence they can reduce dementia risk, so she stays where she is.
Our friends have demonstrated how environmental and medical factors can modify our risk of dementia.
Douglas started in the high risk group, but thanks to regular physical activity, he moved to the medium risk group.
Fiona, who has high blood pressure and doesn’t have regular check-ups to keep it controlled, started with a medium risk but moved into the high risk group.
Heidi and Ivan moved to the low risk group by keeping their brains active with mental and social activities.
This shows the choices we make can influence our risk of dementia just as much as our genetics. Of course, it’s not as simple as our example here, because we each have many different lifestyle and health factors that might be increasing or decreasing our risk.
The best any of us can do to reduce our risk of dementia is live a healthy and active life, and manage vascular risk factors and depression. This can’t guarantee we won’t get dementia, but we’d all prefer to be in the low risk group than the high risk group.
Thanks everyone. Who’s for some fun brain stimulation?
Let’s build something!