Prof. James Vickers
Dementia is a term that we use to refer to a change in functioning from previous levels. The domains that are affected by dementia include your higher cognitive abilities, personality and behaviour. There are many dozens of diseases that will actually cause dementia, and most of these are associated with advanced ageing, although some, particularly with a high genetic predisposition, can occur at much younger ages.
The four major neurodegenerative diseases that cause dementia are Alzheimer’s Disease, Lewy Body Disease, Frontotemporal Dementia and Vascular Dementia. And sometimes these occur singularly and they can also occur in combination. And it’s these four that we’ll focus on in the presentation today.
The major cause of dementia is Alzheimer’s Disease, and this probably accounts for around 50% to 60% of cases. We know that Alzheimer’s Disease is characterised by specific pathological changes that occur inside the brain, and these were originally described by Alois Alzheimer at the beginning of the 20th century. The three changes include those that happen at the macroscopic level, which involves shrinkage or atrophy of the brain, and this can affect particular structures of the cerebral cortex, including the frontal lobe, temporal lobe and parietal lobe. The other two pathological changes occur at the microscopic level, and these are neurofibrillary tangles and amyloid plaques. Amyloid plaques are spherical structures that occur between nerve cells and are comprised of a protein known as A-beta. Now A-beta is a normal protein that you would find in all of our brains, but in Alzheimer’s Disease, it undergoes an abnormal transformation. It forms small fibrils that accumulate together to form plaques, and where plaques form in the brain, they cause damage to nerve cells, particularly the processes of nerve cells, the axons, the dendrites, as well as synaptic connections between those nerve cells. The other major microscopic change that occurs inside the brains of people with Alzheimer’s Disease is the neurofibrillary tangle. Now, within all nerve cells there’s a fine meshwork of filamentous proteins that we refer to as the cytoskeleton. When a nerve cell is affected by Alzheimer’s Disease, this cytoskeleton collapses and is replaced by the neurofibrillary tangle. The main protein that comprises this tangle is an altered form of a normal brain protein we refer to as tau. Now, tangles probably take many years to actually develop within nerve cells, and they seem to follow the initial development of plaques within the brain. They are also very insoluble structures, which means they don’t dissolve very easily. So when a nerve cell dies, usually the tangle is left behind, and we refer to this as a tombstone or ghost tangle. There are new imaging technologies that are being developed for Alzheimer’s Disease that might help us visualise these amyloid plaques and neurofibrillary tangles inside the brains of people while they’re alive. If we combine the data from these new studies with that which has been derived from pathological studies, we now appreciate that there’s a particular sequence of pathological change that occurs inside the brain with Alzheimer’s Disease. It seems likely then that plaques may occur many years, sometimes as many as ten to fifteen years, before you develop overt symptomatology. The plaques appear to precede the neurofibrillary tangles and the neurofibrillary tangles themselves are more closely linked with the loss of synaptic connections between nerve cells, which lead to the pattern of symptoms. In this regard, Alzheimer’s Disease is a degenerative and progressive disorder in that the disease develops from one stage to the next - from a clinical silent period, where plaques develop inside the brain, through to the initial stages of the disease, which can be insidious and often difficult to detect, then through to the progressive deterioration in higher cognitive functions. One of the early cognitive functions that seems to be affected by Alzheimer’s Disease is short-term memory and the ability to form new memories.
导致认知的主要原因是阿尔茨海默病，可能约占50％至60％的病例。我们知道，阿尔茨海默病的特征是在脑内发生特定的病理性变化，这些特征最初在20世纪初由Alois Alzheimer所描述。这三种变化包括在宏观水平发生的改变，其涉及脑的收缩或萎缩，并且影响包括额叶，颞叶和顶叶在内的大脑皮质的特定结构。其他两种病理性改变发生在微观水平，它们是神经原纤维缠结和淀粉样斑块。淀粉样的蛋白斑块是存在于神经细胞之间的球形结构，并由称为A-beta的蛋白质所构成。在我们所有正常的大脑中，A-beta是一种正常的蛋白质。但在阿尔茨海默病患者的大脑中，这种蛋白发生异常的转变。它形成小的原纤维，进而这些原纤维聚集在一起形成斑块，并且这些在脑中形成的斑块对神经细胞，特别是神经轴突和树突以及这些神经细胞之间的突触连接造成损害。在阿尔茨海默病患者脑内发生的另外一个主要的微观变化是神经原纤维缠结。在所有的神经细胞中都有一个由丝状蛋白构成的细丝网络，我们目前称之为细胞骨架。当神经细胞受阿尔茨海默症影响时，该细胞骨架塌陷并被神经原纤维缠结所替代。构成该缠结的主要蛋白质是一种正常脑蛋白的改变形式，我们称为tau蛋白。缠结可能需要许多年才真正在神经细胞内发展，并且它们似乎在脑内的最初的斑块的发展之后形成。它们也是非常不溶的结构，这意味着它们非常不易溶解。因此，当神经细胞死亡时，通常会留下缠结，我们将其称为墓碑或幽灵缠结。有一些为阿尔茨海默病而正在开发的新的成像技术，可能会帮助我们活体观察人类大脑内的这些淀粉样斑块和神经原纤维缠结。如果我们将来自这些新研究的数据与来自病理学研究的数据相结合，现在我们会认识到在阿尔茨海默氏病患者的脑内发生了特定的病理变化序列。斑块似看起来似乎在症状出现之前已经存在了许多年，有时多达十至十五年。斑块似乎出现在神经原纤维缠结之前，并且神经原纤维缠结本身与神经细胞之间的突触连接的丧失更紧密地相关，从而导致症状的产生。在这方面，阿尔茨海默病是一种退行性和进行性疾病，其中疾病从一个阶段发展到下一个阶段 - 从斑块在脑内发展的临床沉默期，直到疾病发生的初始阶段，这个过程可能是隐蔽的并且经常难以检测的，然后进入更高的认知功能逐渐恶化时期。似乎受阿尔茨海默病影响的早期认知功能之一是短期记忆和形成新的记忆的能力。
In Alzheimer’s Disease, we know that particular brain regions are vulnerable to degeneration, and even within those brain regions, certain nerve cells are particularly susceptible. One of the structures of the brain that’s affected early in the disease is the medial temporal lobe, and as this degenerates, you may see some symptoms, such as an inability to form new memories and difficulties generally in short-term memory. But then the disease progresses to other brain regions, to other lobes of the cerebral cortex, and as this occurs you will see difficulties in other higher cognitive areas, as well as behaviour and personality, and this might include planning ability, logical thinking, orientation in space and time, as well as language.
The speed of progression, as well as the age of onset, of Alzheimer’s Disease does vary between individuals. We don’t really understand why this is the case, but it’s likely mainly due to genetic predisposition, but other lifestyle factors may well play a role.
In Alzheimer’s Disease, there are likely to be a range of genetic risk factors that contribute to your relative risk of developing this condition. The best known one, and the one that has the most impact on your risk, is the apolipoprotein E gene. Now, this comes in three variations – Epsilon II, Epsilon III and Epsilon IV. You inherit one version of this gene from each of your parents. Essentially, the more of the Epsilon IV version of this gene you have, the higher risk you have of developing dementia as you get older. In less than 5% of cases, there’s a much stronger genetic predisposition and we often refer to this as familial forms of Alzheimer’s Disease. We know of three genes that carry a range of mutations that can cause familial Alzheimer’s Disease. One of these is the amyloid precursor protein gene, and we know that this is then linked potentially to the production of amyloid beta that forms the plaques in Alzheimer’s Disease.
在阿尔茨海默病中，可能存在一系列遗传风险因素，这些因素会促进您发展这种疾病的相对风险。最著名的一个，对你的风险影响最大的是载脂蛋白E基因。现在，这有三种基因变异 - Epsilon II，Epsilon III和Epsilon IV。你每个人从各自的父母继承这个基因的一个版本。基本上，你如果拥有更多的Epsilon IV版本的基因， 等你变老时你就有更高的发展为老年认知症的风险。在不到5％的病例中，有更强的遗传倾向，我们经常将其称为家族型阿尔茨海默病。我们知道三个携带一系列可导致家族性阿尔茨海默病的突变的基因。其中之一是淀粉样蛋白前体蛋白基因，并且我们知道这可能与在阿尔茨海默病中形成斑块的淀粉样蛋白β的产生有关。
Another cause of dementia is Lewy Body Disease. Now, this is known by a variety of terms, including diffuse Lewy Body Disease, Dementia of the Lewy Body Type and Alzheimer’s Disease with Lewy Bodies. The cardinal pathological feature of Lewy Body Disease is the presence of an abnormal proteinaceous inclusion inside nerve cells called the Lewy Body. Now, the Lewy Body is a spherical structure made up of proteins, fine filaments and lipids. It also occurs as the main pathological feature of Parkinson’s Disease, and we think that Parkinson’s Disease and Lewy Body Disease are related to each other. Some of the clinical features of Lewy Body Disease may well include motor problems that you see in Parkinson’s Disease, such as tremor. Similarly, if you have Parkinson’s Disease for a long period of time, you may then develop cognitive issues that are very similar to what we see in Lewy Body Disease. Inside the brains of people with Lewy Body Disease, you’ll often also see amyloid plaques, and this probably speaks to some kind of interrelationship between Lewy Body Disease and also Alzheimer’s Disease.
Another cause of dementia is Frontotemporal Dementia, and this is really a spectrum of different diseases. Broadly, they’re characterised by dramatic shrinkage, or atrophy, of brain regions, such as the frontal lobe, and the frontal sections of the temporal lobe. The symptomatology of the disease broadly follows the damage to these cortical areas – for example, with frontal lobe damage, comes changes in personality and behaviour, as well as higher cognitive skills, such as planning and judgement. With damage to the temporal lobe, there’s often problems with language and speech production.
认知症的另一个原因是额颞叶痴呆，这其实是一系列不同的疾病。广泛地讲，它们的特征是脑部的急剧收缩或萎缩，例如额叶和颞叶的正面部分。疾病的症状学大致广泛存在于对这些皮质区域的损伤 - 例如，伴随额叶损伤，发生个性和行为上的变化，以及更高的认知技能，例如规划和判断能力。由于颞叶损伤，语言的产生常常出现问题。
Of all of the conditions that cause dementia, frontotemporal dementia probably has the strongest genetic predisposition. So around about 30% to 40% of cases of frontotemporal dementia are likely linked to particular genetic mutations. And because of this genetic predisposition, these cases tend to have a relatively early onset.
Vascular dementia is sometimes known as multi-infarct dementia, and this involves an interruption to the normal blood flow into the brain. In most cases of vascular dementia, this involves damage and disruption to the small blood vessels that penetrate through the brain, particularly in the white matter tracks underlying the cerebral cortex. In other cases of vascular dementia, there might be a series of small strokes occurring in different regions of the brain. Vascular pathology is actually quite common with advanced ageing and this vascular disease can coexist with other forms of dementia, such as Alzheimer’s Disease.
These different forms of dementia are the focus of intense study globally. We are trying to understand the sequence of pathological changes that lead to dementia. In many cases, this is probably largely attributed to advanced ageing, as well as your genetic predisposition, but we’re also interested in how more modifiable risk factors may play out in terms of the disease pathology. Ultimately, we’re interested in therapeutic agents that might modify disease progression, so might have an effect on the specific pathological hallmarks, or it might be that we can look at interventions that might improve on your relative resilience to these dementing disorders.
We can look at figures from perhaps two sources here. One is of course the global observatory in London, which was set up by the ADI some years ago. That observatory, run by Professor Martin Prince, has been collecting data, and these data were actually published by the Alzheimer's Disease International in 2015. The estimate was that there were roughly about 45 to 50 million people, I think the figure they came to was 47.8 or something like that, around the world. More recently there was another publication that’s from the Global Burden of Disease group, which is run from Washington DC. They came to very similar figure, about 45 million, so that’s really the number of people overall in the world, with a diagnosis of dementia.
我们也许可以从两个地方查找全球认知症患者的数据。其中一个当然是伦敦的全球天文台，它是由ADI在多年前建立的。Martin Prince教授一直在用这个天文台收集数据，而这些数据于2015年刊登在了国际阿尔兹海默病期刊上。该数据估计全球有4.5-5千万人被诊断为认知，我认为他们得到的数据应该大约在4.78千万左右。最近，另一份来自华盛顿的全球疾病负担小组的出版物也指出全球有4.5千万人被诊断为认知症。这个数据和之前Martin Price教授他们采集的数据（4.5-5千万）非常接近。所以，全球真的有这么多认知症患者。
But I must emphasise that this is not a precise figure, and for various reasons. One is that the data we have from many countries, is secondary data, we do not have good surveys. Even from high income countries or developed countries, the figures on dementia vary depending upon what criteria have been used, what the sampling strategy has been. This is a very rough guide.
I think there are two points I want to make here. First point is that there is an increase in the number of people, and that is quite a rapid increase projected over the next 30 to 40 years. Primarily that increase is driven by the increase in the total number of people, who are over the age of 60 or 65. We know that dementia increases exponentially with age, and especially after the age of 65, there is a doubling of the number of people with dementia. Every 6 years or 6.3 years to be precise, I think is probably the estimate. The more older people there are, the more people with dementia there will be. We know there are going to be more and more older people around the world.
In particular in the developing countries or low income countries and low and middle income countries, there is going to be a rapid increase, because those populations are ageing now. Whereas in the high income countries, the population has already aged to a significant degree. But ageing is happening very quickly in those countries. In fact they're going to contribute more and more towards people with dementia in the future. That’s really one reason that there is going to be more and more people with dementia around the world. It's projected that by the middle of the century, the number is going to be more than twice as many. One projection is maybe about 150 million people by the middle of the century around the world.
The second point I want to make is that there are some other trends we are seeing. Especially this trend has come from developed countries, high income countries, that in fact the incidence of dementia may actually not be rising, may in fact be falling. I think here we need to distinguish between the overall numbers, the prevalence of dementia, and incidence. By incidence we mean people with a new diagnosis of dementia, so how many new people are coming in to this fold of getting a diagnosis of dementia. There have been some studies from Europe and from North America, which have suggested that in fact the incidence of dementia in the developed countries may be falling, or may have been falling for the last two decades or so, and may continue to fall for some more time. Although we think that that will plateau, sometime in the future.
In particular I want to highlight three studies here. The first study perhaps, is from the UK, which is called the MRC CFAS study. Essentially it was a large study from six centres in the United Kingdom, which was done twice. Once this study was done to look at the overall prevalence of dementia in the UK in the early ‘90s. Then the study was repeated 20 years later, so to see after a generation what has happened. The short message from that study is that what they had projected was that the rate would be about 8.1% 20 years later. But actually the rate that they found on this survey, on this, was much lower, about 6.7%. There were fewer people with dementia than they had projected from the earlier estimates. In fact the total number had not gone up very much, even though the number of people who were at risk, of that old age population, had gone up significantly, suggesting that fewer people were developing dementia than 20 years earlier.
Then there’s another study from The Netherlands, that's the Rotterdam study, and the Rotterdam study is interesting because they've been following people in Rotterdam as they grow older over several years now. They looked at their rates of dementia and here they're looking at new cases, which is the incidence of dementia, 10 years apart. They found that 10 years later, the incidence was lower. Although not significantly lower, but slightly lower, not statistically significant. But a very interesting study that’s been published from the United States and that’s from a place called Framingham in Massachusetts. The audience will be familiar with the Framingham study, which actually is a study of cardiovascular health, which has been going on now for 40 to 50 years.
They started with heart health and now they've gone on to brain health. They've been looking at dementia cases now for about 40 years. They looked at rates in the late ‘70s, and then the ‘80s, ‘90s and the 2000s and see what has happened. They found that each decade, the incidence of dementia has actually gone down, to the extent that over this period of 30 years, there was about a 44% reduction in the incidence or new cases of dementia. So in fact there's both a bad news story and a good news story in this. The bad news story is that overall the number of people with dementia around the world is increasing and is likely to increase. The greatest increase is going to be in low and middle income countries. But high income countries, still there's going to be maybe an increase, but not as much as we had feared in the past. Because there is probably a levelling off or even a slight decline in these people. Unfortunately in the low and middle income countries, this decline is not likely to happen very soon, in fact at this point, there is some suggestion that the rates may be increasing to some extent because of certain risk factors.
We do not know for sure why the numbers in low and middle income countries are increasing. But definitely the major increase is because there are more older people, the life span is increasing so more people are at risk of developing dementia. So that’s the big bulk. But whether there is another contribution being made by factors such as obesity, diabetes, poor metabolic health, cardiovascular disease, stroke, we’re not sure. Because some of these are increasing, unfortunately in many low and middle income countries, with changes with industrialisation, changes in dietary patterns, changes in physical activity levels. Rates of diabetes are increasing, rates of stroke are increasing. This is happening in India, in China, which are major populations really in terms of total world population. It is possible that this will flow on through in terms of rates of dementia in the future. At this point we do not know, but that’s something that we have to watch out for.
Studies that have looked at the changes in prevalence and incidence of dementia across say a 20 year span or over a generation, have tried to hone in to the possible reasons. If you look at the Framingham study, they found that the major change was in vascular dementia, not in Alzheimer's disease, so it is suspected that it could be vascular risk factors, such as better control of hypertension, better control of diabetes, good management of cardiovascular disease. But that did not explain all of the change really.
There is a suspicion that it may be other factors, and starting off with early life factors, such as good education. We find that getting a good education early in life, sets you up for a good health lifestyle, throughout your life. It also gives you protection in terms of cognitive ageing, of decline in your cognitive function as you age. This is evidence that comes from the European studies as well and in fact even from our own study in Sydney. Early education is a significant protective factor. It may work through various different ways. But certainly better control of vascular risk factors, good diet through life, management of obesity, physical activity through life, are all important and maybe all are playing a role in this, in terms of the improvements we are seeing.
I think I should add then, that we suspect that if we are seeing an improvement in the high income countries, in the last two to three decades, we cannot take it for granted. Because it’s very likely that this will level off and then we are also seeing that in our younger populations, in developed countries, rates of obesity are increasing, and poor diet, dietary patterns are increasing as well. It’s possible that we might reverse some of these gains in the future. We cannot actually sit back on our laurels, we have to be vigilant forever.
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.
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.
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!