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In this webinar, Professor Amy Brodtmann explores the strong links between vascular health, brain health and dementia risk, with a focus on women. She highlights key modifiable risk factors, including hypertension, diabetes, dyslipidaemia, sleep disturbance and physical inactivity, and explains why prevention, exercise and cardiovascular risk management are central to protecting cognitive health.
In this webinar, Professor Amy Brodtmann explores the strong links between vascular health, brain health and dementia risk, with a focus on women. She highlights key modifiable risk factors, including hypertension, diabetes, dyslipidaemia, sleep disturbance and physical inactivity, and explains why prevention, exercise and cardiovascular risk management are central to protecting cognitive health.
Duration: 45 min 11 sec
Professor Amy Brodtmann: I’m a stroke and cognitive neurologist. I trained here in Melbourne. I was an Austin baby and did my stroke neurology and then went and did cognitive neurology in Chicago because we couldn’t train as a cognitive neurologist in Melbourne. I have had a lifelong interest in brain health and how vascular risk factors affect late life cognition. So that may explain some of the biases today.
Okay, so let’s get started. Firstly, I just wanted to acknowledge that I do work, live and play on the lands of the Wurundjeri Woi-Wurrung people, the Kulin Nation and beautiful Narrm. And I acknowledge Elders, past, present, emerging, and any First Nations people who may be viewing this today. I’m going to talk about, a little bit about dementia. I’m really going to talk about how we conceptualise dementia and neurodegeneration. Largely because when we went to medical school, I imagine that most of you got zero on neurodegeneration. I certainly did, and I was interested in brains even then.
And so I think I’m going to give you a little bit of the history and I’m going to indoctrinate you into what I think is actually important about dementia. Because it’s not, I think, necessarily how we have conceptualised it in the past. I’m going to really emphasise, as Marita’s just beautifully said, that vascular health is brain health, and that the risks are largely midlife and vascular. And then I’m going to talk a little bit about neuroprotective behaviours. Just really, it’s very iterative, our talks today and repeating and sort of looping back a little. But I will talk a little bit more about exercise because there actually is very good evidence for exercise now.
So this section I always call ‘nuns and orthodoxies’ because it is about the orthodoxies of what dementia risk is and the facts, pathologies, and incidence. And you’ll see why I call it ‘nuns’ in a moment. So just to talk a little bit of how much of a problem this is, now you are all women’s health specialists, and women have been dying of dementia at disproportionate rates globally for centuries. And I think that it’s now very sobering to know that dementia is the leading cause of death in Australia overall. Two years ago, it became the leading cause of death for Australian women. And then last year it is the leading cause of death overall.
So it’s estimated that almost half a million Australians are living with dementia and 1.7 million people are involved in the care of someone living in dementia. That’s in Australia. So that means that all of you will either know someone or be caring for someone who cares for someone with dementia. And I think that that is … I mean, certainly, I mean, I’ve worked with people with dementia, but I’ve also been involved in caring with people with someone with dementia as well.
The number of Australians living with dementia is expected to increase to a million in the next 30 years. 10 million people are diagnosed each year in the world, and women are disproportionately affected by dementia, not just because we’re more likely to get it, but we’re also the people who are largely almost, in some countries, almost exclusively dealing with people, actually caring with people with dementia. So it costs the world about $1.6 trillion, which is the GDP of a moderately sized European nation, which is a lot of money. And I think that, this is a little schematic that I got from the QBI site, the Clem Jones Centre. I think that one of the reasons why I’ve put this up is that you can see that despite the fact that the first cases of dementia pathology were described more than a hundred years ago, 120 years ago, that really it’s just been in the last two decades that we’ve had some idea of really how to diagnose and treat people with dementia. It’s just since the 2000s.
We’ve had advances in the 70s and 80s, which I’ll summarise, but really it’s just going, we’re still harking back to these guys. So I’ve put up pictures of them because they’re really famous. So Alois Alzheimer who described these plaques and tangles in the brains of a woman, a single woman who diagnosed of young onset dementia. She probably had a presenilin mutation. And then it was Oscar Fischer who said we should call it Alzheimer disease. He described it in a group of people with later onset Alzheimer’s disease. And then there was Emil von Kraepelin who put it together and said, “This is Alzheimer’s disease.” I’ve put up Arnold Pick there because I think that he’s important for the pathology of Pick’s disease, which is frontotemporal dementia, which is a different form of a tauopathy.
So the thing about these guys is how good are their moustaches? And obviously you couldn’t have done any research in this field unless you had that mo. I mean, look at Emil Kraepelin’s. Look, that’s amazing. It’s fantastic. And it was quite a deterrent to me because I don’t have a moustache. So the orthodoxies is that I think for the last 100 years, we’ve lived in this age of causal toxic proteins. So 120 years ago, this single case, and then we had the tangles that were described. And again, I’m talking about there are two pathologies that were described in Alzheimer’s disease by Alzheimer, by Fischer, and they are tau and amyloid.
The tangles were described by electron microscopy in the 60s. And then there was a hypothesis of Alzheimer’s which was about neurotransmitter dysfunction, the cholinergic hypothesis. That led to the manufacture 20, 30 years later of donepezil, of Aricept, which is actually still used as a mainstay of symptomatic treatment as well.
And I think that, it wasn’t until ’84 that this potential, or actually ’87, I should say, that the first genetic association was described on chromosome 21, which is obviously, we know people with Down syndrome are at very high risk of Alzheimer’s disease. And then in the 90s, this amyloid hypothesis come out, which is the resurgent and dominant hypothesis of Alzheimer’s disease, that amyloid was the first protein and that everything came after that. So that’s still the hypothesis, and that’s led to the discovery and the use of the current therapies that were only actually approved by the TGA last year, which are the antiamyloid antibodies, donanemab. And we’re going to talk about that a little bit in the case discussions later.
So the ascent of the amyloid hypothesis has been fairly dominant and any Alzheimer talk always has this slide up. And this is a theoretical graph that Clifford Jack devised in 2010 and said, “This is probably what it looks like.” The problem is that you go to talks and this is gospel. This was always a theoretical graph that, we start with the amyloid beta and that we then have tau-mediated neuronal injury and then things follow after that. And this has been revised and revised. And Clifford Jack himself has said that this is theoretical. This is what his conceptualisation is. But you will see it presented as ‘this is what happens in Alzheimer’s disease’.
And so I suppose one of the problems with that is if we go back to the pathologies depicted by those men with the fabulous mos is that tau and amyloid were described, but Alzheimer described vascular degeneration extensively in the brain of Auguste Deter. And he also described incredible and intensive microglial activation. And just for those who aren’t quite sure, the microglia, we don’t have, we can’t get lymphocytes and macrophages into our brains. They’re not allowed. Our brains has its innate immunity and there are a number of immune cells in the brain, the microglia and astrocytes. And these are the guys, the microglia, who actually help with mopping up damage and clearing problems and also probably driving pathology as well, so they can be bad and good.
This is another schematic of potential treatments or targets for dementia, which is a little bit broader. So go back to these pathologies, there’s a number of things that are happening. We know that donanemab and lecanemab, those two drugs that were approved last year, are antiamyloid, but there is now a thinking that, well, maybe we should be looking at the synaptic function, the connections between the brain cells. How are they working? How healthy are they? We should be developing agents that actually help to reduce toxic tau species. We should be developing agents that are good for metabolism and bioenergetics.
And I’ve put a little line through the ones that were tried and found not to be of benefit or haven’t been approved in Australia. And the GLP-1 inhibitors, we certainly know they’re fantastic for prevention, but probably not for treatment. And there are now pretty exciting therapies for neuroinflammation as well, but this is relatively new. You saw that those ideas have taken their time.
So if we think about what actually we know in terms of the epidemiological, so again, those theoretical concepts going back to these pathologies, and then what do we actually know from brain banks? It’s a slightly different picture. This concept of one brain protein causing a whole disease doesn’t really bear out. And if we think about the, and these curves here, this little sort of river bend curve that Marita alluded to before, this also is shown in almost every single dementia talk that you’d ever go to.
And this is from Gil Livingston who published initially, pre-pandemic, the Lancet Dementia Commission. This is from that first paper, no, this is from the second paper, and then revised it in 2024. This is, I think, really did transform how we started thinking about dementia, because the concept of risk factors being, in fact, not just because you’ve got one protein in your brain, was really quite transformative. So we know that there are multiple risk factors, and that if you reduce these risk factors, you probably can prevent up to 45% of dementia cases. That’s obviously theoretical. But look at these. It’s early life, is less education. Now, I’ll speak a bit more about that, but we know that educating girls globally is probably the most important thing we do.
Midlife, the risk factors are really all those vascular risk factors that Marita just spoke about, plus a couple of other things. Reducing traumatic brain injury, because we know traumatic brain injury can lead to persistent inflammation and then dementia, and people with traumatic brain injuries obviously have profound cognitive impairments if they’re severely impaired.
Hearing loss is a really interesting one, and that we didn’t mention that, and we can talk about that a little bit more, but hearing loss in midlife is a reversible risk factor. There’s now good evidence that if we treat people with hearing loss, that they actually will either, their cognition can improve in midlife or that they can reduce their risk of having dementia. And I think that one of the things about hearing loss is that we forget that how much of this environment is actually auditory. Whilst I can tune in or tune out of my voice, we can hear what’s going on. And this is this cognitive stimulation. We are social creatures and we need to be in that social milieu. And I think that hearing loss makes us socially isolated. And in late life, in fact, 5% of dementia risk is social isolation. So I think that it’s not surprising that that’s there. It could be that there’s some hearing losses that neurodegeneration, but that’s not fully understood.
So again, in this paper from the Lancet Dementia Commission in 2024, you can see that the way that we address or possible mechanisms for enhancing or reducing dementia risk are all the things that you’re doing every day. All of the things that we’re doing as health practitioners, it’s reducing diabetes, reducing obesity, stopping smoking. I mean, we don’t … I mean, certainly smoking is a problem in Australia, but because of Sarah’s work, it’s not so much of a problem as in other countries. And another thing that’s really become emergent is air pollution, particularly in some countries in Asia, it’s very problematic.
So the epidemiology says, let’s reduce vascular damage to reduce dementia. Doesn’t talk anything about having that one pathology in the brain that’s causing you to dement later in life. So amyloid and tau are clearly important, but they’re not the only thing. Alzheimer’s disease, cerebro, and cardiovascular disease share the same risk factors, which is why I said at the start that I trained as a stroke neurologist. I think stroke and dementia are intimately linked in some people, but not everyone who has a stroke gets dementia.
The risk factors that I showed before in terms of cardiovascular risk, always, some of the dementia researchers said, “Well, what about early life education? “Because if we go back to that curve, early life education is problematic if you’re not educated. And they said that’s cognitive resilience that’s actually building up our brain reserve. And maybe it is, but we know that education is one of the greatest determinants of health literacy. It’s a determinant of socioeconomic status as well, which we know in turn reflects your general health and your dementia risk. So I don’t think it’s entirely due to cognitive resilience.
All of these pivotal studies have shown that midlife vascular disease is the strongest risk factor for late life dementia, particularly hypertension. Globally, hypertension is the greatest risk factor for dementia. The cognitive effects such as slowed speed of processing and executive impairments, ability to make decisions and change sets, we can see in non-demented people who’ve had as little as three to five years of hypertension. So these microvascular effects are manifesting even before we know it.
And we know that treating these risk factors, and there’ve been big studies like PROGRESS, which was a study for people with hypertension, intensive treatment, and SPRINT-MIND, which was for people with diabetes. We know the people who are on treatment probably have a reduced risk of dementia, and I’ll talk about that more with individual risk factors in a moment. So this healthy lifestyle is associated with a lower dementia risk and slower cognitive decline.
So now we get to the nuns, and that’s why I call this part of the talk ‘nuns and orthodoxies’, because my favourite pathology brain bank is the religious order studies. It’s now morphed into the ROS, the religious order studies and the Rush Memory and Ageing Project, but the ROS was always referred to as the Nun study. And this is a study that has been going since the ’90s in Chicago and Illinois. And they published that women with strokes had poorer cognitive function and a higher prevalence of dementia than those without them.
And probably you in the audience, this is 30 years olds, are saying, “Well, yeah, I mean, that makes sense, is vascular risk factors.” But this was huge then. This was when the amyloid hypothesis was really resurgent and people were just saying there is just one brain pathology. So the other thing that they found is that, when they looked at these women who had donated their brains, and they were older, they found that amyloid status, the amount of amyloid you had in your brain, actually bore little correlation with your cognitive profile when you died. So these are brain banks, women who donated their brains.
There was especially high incidence of dementia in women with small vessel disease, diabetes, hypertension risk factors, and microvascular disease. And the severity of dementia correlated more with a number of brain infarcts than the amyloid protein deposition. And this was pretty huge and very hotly debated by the people who were saying, “No, it’s all about the amyloid.” And it led people to say, “Well, at least it’s the initiator or the stimulator or additive contributor to neurodegeneration.” And people are still kind of hedging their bets because that hypothesis is so dominant.
But we know that when you die at the age of 70 or 80 or 90, that you have lots of stuff in your brain. The co-pathologies are the norm in normal ageing and dementia. So these women from the ROSMAP study, nuns who were followed over their life, and these were all college-educated women, but they lived their lives. They smoke and drank. Not all of them, but some of them. And when they died, they were either classified as having normal cognition because they had cognitive assessments over their lives, mild cognitive impairment or Alzheimer’s disease.
And no matter what you were cognitively, you still have pathology in the brain. And they found that almost no-one had one pathology. So whilst Alzheimer’s was the most frequent pathology, plaques and tangles, amyloid and tau, that they had multiple pathologies in the brain. It rarely occurred in isolation. There were multiple different combinations, and whilst AD pathology accounted for most of the cognitive loss, the rest of it was really accounted for by these: by strokes, by CAA, cerebral amyloid angiopathy, which is getting a lot of discussion now because it causes microbleeds and it’s actually a small vessel disease. Athero and arteriolosclerosis, hardening of the large and small arteries of the brain. And then in fact, this cognitive loss associated with specific neuropathologies was to a large extent driven by vascular pathology. So that’s my nun study.
And you can see that I forgot to tell you about this guy, and Lewy bodies are really important too. And you’d see more of Lewy bodies. And we don’t often talk about Lewy, which is interesting. And I think it’s because he doesn’t have a mo. And I think that we’ve just, he didn’t have that magnificent mo, so these Lewy bodies … Yeah, we could draw one in for him, but he’s very mo-less, in all the pictures. Okay. The other thing that really argues … Yes, very, very mo-less.
The other thing that really argues that these vascular risk factors are important is that whilst we talk about the huge problem that dementia in the world is going to cause, is causing now, we know that dementia incidence, not prevalence, prevalence is skyrocketing, incidence is declining. So I’ll just say that again, dementia incidence is declining globally. Some studies have found about a 26% drop in dementia over the last decade with more pronounced declines in women, so it’s great news. And it may be because these sex specific differences are starting to emerge.
We now know that women who’ve got cardiovascular risk factors are one and a half times more likely to get Alzheimer’s disease, not so much vascular cognitive impairment and dementia. Men tend to get that. There’s an average decrease of 13% per decade over the last 30 years, and people in more recent birth cohorts have a lower risk of developing dementia at any given age compared to previous generations. So this is fabulous news. This is because of all the work that you are doing and we’re doing globally. And you can see that this has been shown in studies in mainly high and middle income countries, but in several countries in Europe, in the UK, in the US, in Canada, and also in Korea, Japan, and not so much in China. Because China, there’s still a big problem with vascular risk factors. So it’s good news that we can actually treat or maybe prevent.
This paper also came out in the Lancet Public Health again from the Lancet Commission Group. And it was looking at pooled data and meta-analyses of dementia incidence. And they showed that changes in dementia prevalence and incidence had been fairly well documented. And they looked at population attributable fractions of risk, which is what those Lancet commission curves were, the PAFs of different risk factors. They found that overall lifestyle interventions such as compulsory education and reducing rates of smoking probably were reducing incidence in the world. They hypothesised that, obviously it’s not causal.
So what’s come up more recently though, and there’s a number of studies. So we’ve known this for 20 years, that vascular risk factors, but we’re now seeing in the pathology, again, my ROSMAP study, where this time there were 1,500 people that had donated their brains, and they looked at trends across birth epoch. So this is starting from a hundred years ago, you were born in 1905 or up to 1930, and they found something that I think is really interesting. They found that in their people, there was no difference in the prevalence of who actually was given a diagnosis of Alzheimer’s disease or who had mean global pathologies, so the Alzheimer’s pathologies were still there, but they found that there was a big reduction in, sorry, I’ll go to this, atherosclerosis and arteriolosclerosis.
So what they found is that the pathologies were, so dementia incidence was declining, Alzheimer’s diagnosis was declining. They still had the same amount of Alzheimer’s pathologies in the brain, but they had less vascular pathologies. So they concluded from this, this is Julie Schneider’s group and David Bennett’s, and he doesn’t want to rock the boat, I don’t think. She said that the time of, improvements in time were probably associated with improved resilience to pathology. That is cognitive resilience, presumably, you’re better at having this in your brain, but you don’t get dementia, but also the vessel pathologies were markedly lower.
I would interpret this, that they didn’t get a diagnosis of dementia because their vessel pathologies were better. And this is from Grodstein from two years ago, three years ago now. Vascular pathologies are declining in brain bank participants. So Marita’s already spoken about this, so very thankfully I won’t need to go into it, but just to iterate, cognitive impairment and dementia are often used differently by members of the community. And I think you all are aware that people come in with different meanings of these terms. ‘Subjective cognitive impairment’ or ‘subjective cognitive complaints’ is the term we use for people who experience cognitive symptoms. So it has no other value. It’s just saying, this is, I’ve got this problem.
But we know now these people were often dismissed, because they’re often women. We know now that people who come in with a subjective cognitive complaint actually are at higher risk of developing cognitive decline. They are experiencing something and noticing something. I think one of the issues is that people who truly do have dementia, in my clinic, probably at least less than 50% think that they have a problem. So when you’d have dementia, insight is affected as well. So it’s a very different thing. These people are noticing the problems. And brain fog absolutely falls into this category, but so does every major life experience. I think that all of us have experienced major life events when we’ve had loss of a partner, child, family member, when we’ve been under extreme stress, sleep deprived, when we’ve been breastfeeding or postpartum, your brain does just not work. And I think that subjective cognitive impairment can have, as Marita said, many, many, many causes.
But ‘mild cognitive impairment’ is a research term. I’m just going to emphasise that. It was a research category that Ron Petersen devised to say, “Well, these are people who are at risk of developing dementia.” We now use it as a diagnosis. I don’t like it as a diagnosis. I’d like to say, what’s wrong with you, that you have depression or that you have sleep impairments. It’s a research category for people with cognitive impairments. It can be used as a diagnosis, it’s just not my thing.
‘Dementia’ is the term we use when people have progressive cognitive impairments that are affecting their ability to function. Most dementia is due to degenerative processes in the brain, and these can cause neurodegeneration. There are some dementias that you can get after getting Korsakoff syndrome or multiple strokes that all happen at once or severe autoimmune cephalitis that have occurred just really in a short space of time, but in general, they’re progressive neurodegenerative processes.
And we detect neurodegeneration mostly on MRI scans in 2026. Certainly CT scans are fine, not everyone can have an MR. And we see lots of things. We see atrophy and we see changes in white matter, which are white matter hyperintensities. The full term is ‘white matter hyperintensities of presumed vascular origin’ because there’s lots of causes for white matter hyperintensities. We see them in MS, but they’re demyelination. We see strokes, we see bleeds. The changes that we see are these vascular changes, or we see atrophy. PET scans, which we can do now, and certainly as specialists, I’m allowed to order up to three in a person’s lifetime, Medicare rebatable PET scans, FDG PET scans, to look for changes if I’m suspecting a diagnosis of Alzheimer’s dementia. So they are great, and they show us the pattern of hypometabolism, the pattern of neurodegeneration.
There are now PET scans, and you will be getting a lot of questions about this, I imagine, that allow us to image amyloid and tau. Tau’s just research, but you can pay for an amyloid scan. So people will come to see you and ask, “Can I detect this brain pathology in life?” unlike the Nun study, and we can, that is about $2,000. So most people don’t want them, but there’s a group of people who are very interested. The big transformation in this space, and again, Marita and I talk about this in the cases, is that we’ve been able to measure brain proteins via a lumbar puncture, via CSF for decades. There’s a lab at the Florey that’s been doing it for decades. But we can measure brain-derived proteins, so from our brain, in just a normal blood test now. This is huge. This is due to big change in single molecule assays, extraordinary ultra, ultra sensitive assays, and it’s really transforming how we think about diagnosis of dementia, but we’ll speak about that next.
So I’m just going to talk a little bit about brain volumes. And again, Maria introduced this, that paper that came out last year that was, “Oh my god, you’ve hit menopause, that’s it. Your brain’s shrunken. It’s a tiny walnut and it’s a disaster.” And as Marita said, it’s not that bad. And I agree that that discussion was excellent. And I read the conversation piece last year, and I think those authors were really going, “Oh my god, I’m walking this back.” Our brains, sadly, well, not sadly, but truly, reach peak volume in the third or fourth decades. That’s in our 20s and our 30s. And they decline after that, which is sad, but so does everything. I mean, our skin gets thinner, we lose disc space, we get shorter. It doesn’t mean that we’re losing brain cells. It doesn’t mean that we’re losing brain cells.
There’s been a number of studies looking at brain volume and cognition, a lot of them from the UK biobank. So again, a really fantastic study done in the UK, half a million people, a lot of them with MRI, data linkage, extraordinary, a little biassed in terms of diversity and who’s actually volunteered for this study. And we know that when we look at brain volumes, that yes, that menopause is associated with grey matter decline, but most of them have been done by people who are more interested in the mental health. So the lens has been, let’s look at their mental health issues and let’s see what’s happening with that. Oh, and let’s look at their brains as well. And low and behold, they’ve found that menopause is associated with a decline. But our brains do lose more volume in our 40s, 50s, and 60s than they lost in our 20s and 30s. So it’s not that surprising.
What they’ve shown, and that the spin of this, was that HRT doesn’t help. MHT doesn’t help. So your brain’s going to shrink. It’s going to be a walnut and taking the drugs don’t help, but they don’t also hurt you either. So it’s actually part of our natural history of our brains. It’s not associated with increased risk of dementia. There’s no effect on brain volumes of MHT, HRT, either way. So if women want to take it because it suits them because they’ve got sleep problems, well take it. If we think of the scare about three years ago where they said, “Oh my god, you’ve got an increased risk of dementia because you’re on MHT,’ well, it’s not true.
We know that those midlife cardiovascular risk factors determine our brain health. And when they looked at that and brain volumes, it was the cardiovascular risk factors that were largely determining how quickly you lost your brain volume. Although it feels like you lose your brain sometimes.
There are some data from Australian studies, and I think we often, because of the UK Biobank is so big, 500,000 people, 125,000 women, that we’ve been running, Lorraine Dennerstein’s been running this women’s healthy ageing project from last decade. Cassandra Szoeke has taken it over, and they’ve been looking at, now, small numbers of women who are still in the study who’ve got, with an interest in cognitive profiles and dementia risk. And again, they’ve borne out very similar. So these are Australian women. These are mostly Victorian women. Those people who’ve got impairments and smaller brain volumes, nothing to do with their hormones, it’s to do with their hypertension, their physical inactivity, and their dyslipidaemia. So really important that we treat those.
And again, this was this Zulsdorf study that showed that women have more mental health problems in menopause, and they reduce their grey matter more, but in fact, the HRT isn’t affecting them either way.
The risks. So again, I know I am really banging on about this, but I cannot emphasise how important these risk factors are. Hypertension is arguably the greatest global driver of dementia. So I think that we really need to be, if someone’s hypertensive, and I was interested to hear those renewed, the change from 140 on 90 to maybe 130 on 80, maybe we should be thinking more, we should be more aggressive with our women. I mean, obviously they cause side effects, but the drugs are so great now. Hypertension affects women at all life stages. Their rates of hypertension increase with age and postmenopausal women have the highest rates. In fact, in our 50s is when all of those risk factors come to roost, and they do in men too. So it’s not surprising that the hypertension rates start to bump up. No doubt that the menopause affects it.
I often, when I’m trying to convince someone in clinic to take her anti-hypertensives, I say to them, “You know that if you don’t have blood pressure problems, you’re going to live five years more.” So non-hypertensive women have five years longer lifespans, these are global, these are epidemiological studies, than those with hypertension. It can be controlled. And in most women, it can be controlled very easily with a single therapy. And interestingly, over the pandemic in Canada, they found that there was, because of health anxiety and isolation, that a lot of, there was actually a reduction in risk reduction for women, particularly the antihypertensives, down 20%. And they have shown that in their health data, public health data, there’s been an increase in cardiovascular deaths and hospitalisation. So the drugs really work short term and long term as well to prevent dementia.
We can speak more about obesity and insulin resistance. It’s interesting, we had a dinner last year with Sue Davis, who’s the menopausal guru in Australia. And she was saying that perimenopausal weight gain actually starts five to 10 years prior to menopause, at one kilo a year. So it’s not just over the menopause. The menopause is associated with a distribution in central, to central body fat, which anyone who’s going through this will have experienced, but we also do less. We have a decrease in energy expenditure that’s associated with weight gain. We get insulin resistance. And apart from hypertension, insulin resistance is a real problem. Some people talk about insulin resistance being a profound driver of amyloid pathologies. I think there is good evidence for that. We know that that’s associated with that syndrome X. I don’t think we call that anymore. But this proatherogenic lipid profile, those LDLs are really the baddies, not just for cardiovascular disease, but for our brains.
And we know that while HRT/MHT can help with body fat deposition, it’s not associated with weight loss. So it can redistribute where we put on the weight, but we don’t get weight loss. So it’s not going to actually help on itself. Again, not for or against, just saying that I think there are some people who believe that it’s going to solve all of the problems associated with the menopause. It’s just not.
Sorry, this is a slide from a public lecture I gave. So it is true that LDLs are the baddies again when it comes to our brains with dementia risk. In fact, it’s one of the ones that was added to those curves I showed you before. And during the menopause, our lipid profile changes, as Marita said. The other problem with this abnormal fats and sugars and sleep is that the more obese we are, the more likely we are, sorry, to have sleep apnoea. And menopause is associated with profound sleep disturbance. Don’t forget that some of that might be sleep apnoea. And I think that sleep treatment is a really important thing. I, obviously I run a cognitive clinic or clinics, I’m often referring people for sleep studies. You can do them in the community now. I have a 60% positive hit rate. And we know that in people with stroke, for example, 60% as well have sleep apnoea and they’re fine. They think they’re fine. And these are people who probably need treatment.
So it’s such a silent epidemic and it’s a real issue with the menopause and that they also increase in men as well in their 50s, but definitely in women. So I put this, I took this from the Health Week for Jean Hailes last year just to show how brilliantly … So this is the week that you did, the first week of September. Everything is what we’ve just spoken about: getting checked, taking the lead, making sure that you’ve got the right knowledge, being heart smart, and talking also about pain, which is another unmet need in women, and being kind to your mind. And I haven’t really spoken about mental health, but it’s a massive issue as well. And it is on that curve.
So just to finish with this, because it was a question earlier. So what reduces blood sugar, blood pressure, LDL, obesity, and improves our mood, our sleep, and our longevity? And it’s not HRT, although it can help. And it’s not Sudoku, because all my patients ask me about brain exercises, and because it doesn’t do anything. I have had people who have really demented completing their … I can’t do them, but they can do them, and they’ve got dementia and I don’t, yet.
So it’s exercise, obviously. So let’s talk about brain health and neuroprotective lifestyles at every stage. So I’m going to just talk about physical activity. Because I think that, I’m a big fan of exercise prescriptions. I think they’re the neglected prescription. I think we’re not talking about this because it’s so much else to talk about. There’s so many other things that we need to be discussing, but I think that this is the neglected prescription.
So physical activity for brain health. Physical activity, particularly huff and puff exercise, but resistance as well, is so important. It increases brain-derived neurotrophic factor, which actually does exactly that. It says to the cells, grow. Synapses, do things. It increases VGF, which is a endothelial vascular growth factor. It’s healthy for our blood vessels. It’s the only thing that increases hippocampal volume or neurogenesis in our memory centres in our brain. The only adult behaviour that we know continues to do that. It increases our cerebral blood flow. It reduces our vascular risk factors. We know it’s reduced. It’s associated with reduced cognitive decline. It improves our cognition.
So physical activities and sedentary behaviours, so physical inactivity and sedentary behaviour. So there’s two different things, obviously sitting, lying, sedentary behaviours, they’re bad for the brain. But also not doing any physical activity is bad for the brain. So higher levels of physical activity, lower levels of sedentary behaviours are associated with better global function in older adults.
So this is something that we can say is good for you in midlife because it does help with sleep and it helps with mood as well, but it’s also going to be good for you when you get older. When I look at the effect sizes, I didn’t show a definition of that then, but we know that the effects are greatest for moderate to vigorous physical activity, and time spent active, or total physical activity. That more physical activity, to a point, so ultra marathons are not good for your brain, not good for your heart, not good for your brain, but more physical activity and higher intensity as well. Sadly, for those of us who don’t love HIIT, facts are there, you just got to suck it up and do it, that are most beneficial for global cognitive function. And lifelong physical activity is strongly associated with dementia risk.
Evidence is probably even stronger for women, more for women than for men. And I think that that’s also been neglected. It’s important to do resistance and cardiorespiratory exercise, and it’s good for our heart, our bones, our brain. It’s good for everything. We looked at people after stroke with a variety of tricksy imaging methods, and we showed that physical activity after stroke is associated with better brain connectivity in our attention networks. It also reduces those white matter hyperintensities as well. So you can actually have brain health at any stage. And we did a study because we found that after stroke, particularly, women and men, but particularly women, lost brain volumes at a much higher rate than people who had not had stroke. So we need to be really implementing these strategies at those at risk. Just because you’ve had a heart attack, you wouldn’t say, “Oh, you shouldn’t do any exercise.” I think sometimes with people, we say, “Oh, well, perhaps those things aren’t so important.”
We did this study where we looked at two arms, cardiorespiratory versus a balance and stretching. And we found that whilst there was no difference in brain volume change between exercise groups, their brains shrank at the same rates, those people who were in the cardiorespiratory group had faster speed of processing, their brains worked faster, and they had better global function than those in the balance and stretching. So HIIT does work. A colleague, James Broach, is comparing sedentary people who’ve never exercised middle-aged adults, compared, looking at two different ways of delivering exercise, HIIT and moderate intensity cardiovascular training. And we know that they’re finding similar things as well.
But we also know that less intensive therapies can work, and there’s certainly benefits for a yoga intervention that we’ve seen in stroke survivors. So I think this is the future of brain health. It’s biomarkers, it’s exercise, sorry, if you don’t like it, it is, and advocacy. So I’m thinking that as we’ve heard earlier, that we really need to be thinking about the risk measures that we’re going, and it’s all those things that we’ve discussed, blood pressure and smoking and cardiovascular risk factors and inactivity.
We can measure the brain better now with blood tests and with cognitive tests, as well as with brain imaging, which is my thing. We can assign people into different tiers, if you like. They’re great, they may be at risk or they’re impaired, and then we can actually do targeted prescriptions for brain health optimisation. And some of that will be exercise prescriptions. And when I do public talks, I always end with a few pictures, with a bit of inspo, and these are some people who are marathon runners in their 80s and 90s. I mean, this guy, Ed, did a sub 4 hour marathon at 82. I could not do a sub 4 hour marathon. Take me two days. And this woman’s 90 and she did it in just over seven minutes. I’m a yogi, and so I like to put up pictures. This woman died at 103 and she was the oldest instructor in the world. This guy is 105. This man is doing this at 105, so age is no limit.
So vascular health is brain health, is brain health, is vascular health, for mid to late life. Whilst your vascular risk increases over and after the menopause, the risks can be managed. MHT does not affect your brain health risk either way. It’s good news for those who need it, good news for those who can’t take it or choose not to. Stretching, balance, resistance exercise, yoga and Tai Chi all demonstrate brain benefits. So do what moves you and your patients and consider exercise prescriptions.
And again, and we’ll talk about this a little bit more, we need to rethink our models of care, what’s best suited to our medical systems and communities and cultures. I’d like you all to be brain health champions and ambassadors, and really looking forward to the launch of the women’s brain care clinics at Jean Hailes.
And this is a picture from me. I finished my yoga teacher training last year, and there we are in front of our mandala. I think we should all get up and move now. Thank you.
End of transcript
Okay, so let’s get started. Firstly, I just wanted to acknowledge that I do work, live and play on the lands of the Wurundjeri Woi-Wurrung people, the Kulin Nation and beautiful Narrm. And I acknowledge Elders, past, present, emerging, and any First Nations people who may be viewing this today. I’m going to talk about, a little bit about dementia. I’m really going to talk about how we conceptualise dementia and neurodegeneration. Largely because when we went to medical school, I imagine that most of you got zero on neurodegeneration. I certainly did, and I was interested in brains even then.
And so I think I’m going to give you a little bit of the history and I’m going to indoctrinate you into what I think is actually important about dementia. Because it’s not, I think, necessarily how we have conceptualised it in the past. I’m going to really emphasise, as Marita’s just beautifully said, that vascular health is brain health, and that the risks are largely midlife and vascular. And then I’m going to talk a little bit about neuroprotective behaviours. Just really, it’s very iterative, our talks today and repeating and sort of looping back a little. But I will talk a little bit more about exercise because there actually is very good evidence for exercise now.
So this section I always call ‘nuns and orthodoxies’ because it is about the orthodoxies of what dementia risk is and the facts, pathologies, and incidence. And you’ll see why I call it ‘nuns’ in a moment. So just to talk a little bit of how much of a problem this is, now you are all women’s health specialists, and women have been dying of dementia at disproportionate rates globally for centuries. And I think that it’s now very sobering to know that dementia is the leading cause of death in Australia overall. Two years ago, it became the leading cause of death for Australian women. And then last year it is the leading cause of death overall.
So it’s estimated that almost half a million Australians are living with dementia and 1.7 million people are involved in the care of someone living in dementia. That’s in Australia. So that means that all of you will either know someone or be caring for someone who cares for someone with dementia. And I think that that is … I mean, certainly, I mean, I’ve worked with people with dementia, but I’ve also been involved in caring with people with someone with dementia as well.
The number of Australians living with dementia is expected to increase to a million in the next 30 years. 10 million people are diagnosed each year in the world, and women are disproportionately affected by dementia, not just because we’re more likely to get it, but we’re also the people who are largely almost, in some countries, almost exclusively dealing with people, actually caring with people with dementia. So it costs the world about $1.6 trillion, which is the GDP of a moderately sized European nation, which is a lot of money. And I think that, this is a little schematic that I got from the QBI site, the Clem Jones Centre. I think that one of the reasons why I’ve put this up is that you can see that despite the fact that the first cases of dementia pathology were described more than a hundred years ago, 120 years ago, that really it’s just been in the last two decades that we’ve had some idea of really how to diagnose and treat people with dementia. It’s just since the 2000s.
We’ve had advances in the 70s and 80s, which I’ll summarise, but really it’s just going, we’re still harking back to these guys. So I’ve put up pictures of them because they’re really famous. So Alois Alzheimer who described these plaques and tangles in the brains of a woman, a single woman who diagnosed of young onset dementia. She probably had a presenilin mutation. And then it was Oscar Fischer who said we should call it Alzheimer disease. He described it in a group of people with later onset Alzheimer’s disease. And then there was Emil von Kraepelin who put it together and said, “This is Alzheimer’s disease.” I’ve put up Arnold Pick there because I think that he’s important for the pathology of Pick’s disease, which is frontotemporal dementia, which is a different form of a tauopathy.
So the thing about these guys is how good are their moustaches? And obviously you couldn’t have done any research in this field unless you had that mo. I mean, look at Emil Kraepelin’s. Look, that’s amazing. It’s fantastic. And it was quite a deterrent to me because I don’t have a moustache. So the orthodoxies is that I think for the last 100 years, we’ve lived in this age of causal toxic proteins. So 120 years ago, this single case, and then we had the tangles that were described. And again, I’m talking about there are two pathologies that were described in Alzheimer’s disease by Alzheimer, by Fischer, and they are tau and amyloid.
The tangles were described by electron microscopy in the 60s. And then there was a hypothesis of Alzheimer’s which was about neurotransmitter dysfunction, the cholinergic hypothesis. That led to the manufacture 20, 30 years later of donepezil, of Aricept, which is actually still used as a mainstay of symptomatic treatment as well.
And I think that, it wasn’t until ’84 that this potential, or actually ’87, I should say, that the first genetic association was described on chromosome 21, which is obviously, we know people with Down syndrome are at very high risk of Alzheimer’s disease. And then in the 90s, this amyloid hypothesis come out, which is the resurgent and dominant hypothesis of Alzheimer’s disease, that amyloid was the first protein and that everything came after that. So that’s still the hypothesis, and that’s led to the discovery and the use of the current therapies that were only actually approved by the TGA last year, which are the antiamyloid antibodies, donanemab. And we’re going to talk about that a little bit in the case discussions later.
So the ascent of the amyloid hypothesis has been fairly dominant and any Alzheimer talk always has this slide up. And this is a theoretical graph that Clifford Jack devised in 2010 and said, “This is probably what it looks like.” The problem is that you go to talks and this is gospel. This was always a theoretical graph that, we start with the amyloid beta and that we then have tau-mediated neuronal injury and then things follow after that. And this has been revised and revised. And Clifford Jack himself has said that this is theoretical. This is what his conceptualisation is. But you will see it presented as ‘this is what happens in Alzheimer’s disease’.
And so I suppose one of the problems with that is if we go back to the pathologies depicted by those men with the fabulous mos is that tau and amyloid were described, but Alzheimer described vascular degeneration extensively in the brain of Auguste Deter. And he also described incredible and intensive microglial activation. And just for those who aren’t quite sure, the microglia, we don’t have, we can’t get lymphocytes and macrophages into our brains. They’re not allowed. Our brains has its innate immunity and there are a number of immune cells in the brain, the microglia and astrocytes. And these are the guys, the microglia, who actually help with mopping up damage and clearing problems and also probably driving pathology as well, so they can be bad and good.
This is another schematic of potential treatments or targets for dementia, which is a little bit broader. So go back to these pathologies, there’s a number of things that are happening. We know that donanemab and lecanemab, those two drugs that were approved last year, are antiamyloid, but there is now a thinking that, well, maybe we should be looking at the synaptic function, the connections between the brain cells. How are they working? How healthy are they? We should be developing agents that actually help to reduce toxic tau species. We should be developing agents that are good for metabolism and bioenergetics.
And I’ve put a little line through the ones that were tried and found not to be of benefit or haven’t been approved in Australia. And the GLP-1 inhibitors, we certainly know they’re fantastic for prevention, but probably not for treatment. And there are now pretty exciting therapies for neuroinflammation as well, but this is relatively new. You saw that those ideas have taken their time.
So if we think about what actually we know in terms of the epidemiological, so again, those theoretical concepts going back to these pathologies, and then what do we actually know from brain banks? It’s a slightly different picture. This concept of one brain protein causing a whole disease doesn’t really bear out. And if we think about the, and these curves here, this little sort of river bend curve that Marita alluded to before, this also is shown in almost every single dementia talk that you’d ever go to.
And this is from Gil Livingston who published initially, pre-pandemic, the Lancet Dementia Commission. This is from that first paper, no, this is from the second paper, and then revised it in 2024. This is, I think, really did transform how we started thinking about dementia, because the concept of risk factors being, in fact, not just because you’ve got one protein in your brain, was really quite transformative. So we know that there are multiple risk factors, and that if you reduce these risk factors, you probably can prevent up to 45% of dementia cases. That’s obviously theoretical. But look at these. It’s early life, is less education. Now, I’ll speak a bit more about that, but we know that educating girls globally is probably the most important thing we do.
Midlife, the risk factors are really all those vascular risk factors that Marita just spoke about, plus a couple of other things. Reducing traumatic brain injury, because we know traumatic brain injury can lead to persistent inflammation and then dementia, and people with traumatic brain injuries obviously have profound cognitive impairments if they’re severely impaired.
Hearing loss is a really interesting one, and that we didn’t mention that, and we can talk about that a little bit more, but hearing loss in midlife is a reversible risk factor. There’s now good evidence that if we treat people with hearing loss, that they actually will either, their cognition can improve in midlife or that they can reduce their risk of having dementia. And I think that one of the things about hearing loss is that we forget that how much of this environment is actually auditory. Whilst I can tune in or tune out of my voice, we can hear what’s going on. And this is this cognitive stimulation. We are social creatures and we need to be in that social milieu. And I think that hearing loss makes us socially isolated. And in late life, in fact, 5% of dementia risk is social isolation. So I think that it’s not surprising that that’s there. It could be that there’s some hearing losses that neurodegeneration, but that’s not fully understood.
So again, in this paper from the Lancet Dementia Commission in 2024, you can see that the way that we address or possible mechanisms for enhancing or reducing dementia risk are all the things that you’re doing every day. All of the things that we’re doing as health practitioners, it’s reducing diabetes, reducing obesity, stopping smoking. I mean, we don’t … I mean, certainly smoking is a problem in Australia, but because of Sarah’s work, it’s not so much of a problem as in other countries. And another thing that’s really become emergent is air pollution, particularly in some countries in Asia, it’s very problematic.
So the epidemiology says, let’s reduce vascular damage to reduce dementia. Doesn’t talk anything about having that one pathology in the brain that’s causing you to dement later in life. So amyloid and tau are clearly important, but they’re not the only thing. Alzheimer’s disease, cerebro, and cardiovascular disease share the same risk factors, which is why I said at the start that I trained as a stroke neurologist. I think stroke and dementia are intimately linked in some people, but not everyone who has a stroke gets dementia.
The risk factors that I showed before in terms of cardiovascular risk, always, some of the dementia researchers said, “Well, what about early life education? “Because if we go back to that curve, early life education is problematic if you’re not educated. And they said that’s cognitive resilience that’s actually building up our brain reserve. And maybe it is, but we know that education is one of the greatest determinants of health literacy. It’s a determinant of socioeconomic status as well, which we know in turn reflects your general health and your dementia risk. So I don’t think it’s entirely due to cognitive resilience.
All of these pivotal studies have shown that midlife vascular disease is the strongest risk factor for late life dementia, particularly hypertension. Globally, hypertension is the greatest risk factor for dementia. The cognitive effects such as slowed speed of processing and executive impairments, ability to make decisions and change sets, we can see in non-demented people who’ve had as little as three to five years of hypertension. So these microvascular effects are manifesting even before we know it.
And we know that treating these risk factors, and there’ve been big studies like PROGRESS, which was a study for people with hypertension, intensive treatment, and SPRINT-MIND, which was for people with diabetes. We know the people who are on treatment probably have a reduced risk of dementia, and I’ll talk about that more with individual risk factors in a moment. So this healthy lifestyle is associated with a lower dementia risk and slower cognitive decline.
So now we get to the nuns, and that’s why I call this part of the talk ‘nuns and orthodoxies’, because my favourite pathology brain bank is the religious order studies. It’s now morphed into the ROS, the religious order studies and the Rush Memory and Ageing Project, but the ROS was always referred to as the Nun study. And this is a study that has been going since the ’90s in Chicago and Illinois. And they published that women with strokes had poorer cognitive function and a higher prevalence of dementia than those without them.
And probably you in the audience, this is 30 years olds, are saying, “Well, yeah, I mean, that makes sense, is vascular risk factors.” But this was huge then. This was when the amyloid hypothesis was really resurgent and people were just saying there is just one brain pathology. So the other thing that they found is that, when they looked at these women who had donated their brains, and they were older, they found that amyloid status, the amount of amyloid you had in your brain, actually bore little correlation with your cognitive profile when you died. So these are brain banks, women who donated their brains.
There was especially high incidence of dementia in women with small vessel disease, diabetes, hypertension risk factors, and microvascular disease. And the severity of dementia correlated more with a number of brain infarcts than the amyloid protein deposition. And this was pretty huge and very hotly debated by the people who were saying, “No, it’s all about the amyloid.” And it led people to say, “Well, at least it’s the initiator or the stimulator or additive contributor to neurodegeneration.” And people are still kind of hedging their bets because that hypothesis is so dominant.
But we know that when you die at the age of 70 or 80 or 90, that you have lots of stuff in your brain. The co-pathologies are the norm in normal ageing and dementia. So these women from the ROSMAP study, nuns who were followed over their life, and these were all college-educated women, but they lived their lives. They smoke and drank. Not all of them, but some of them. And when they died, they were either classified as having normal cognition because they had cognitive assessments over their lives, mild cognitive impairment or Alzheimer’s disease.
And no matter what you were cognitively, you still have pathology in the brain. And they found that almost no-one had one pathology. So whilst Alzheimer’s was the most frequent pathology, plaques and tangles, amyloid and tau, that they had multiple pathologies in the brain. It rarely occurred in isolation. There were multiple different combinations, and whilst AD pathology accounted for most of the cognitive loss, the rest of it was really accounted for by these: by strokes, by CAA, cerebral amyloid angiopathy, which is getting a lot of discussion now because it causes microbleeds and it’s actually a small vessel disease. Athero and arteriolosclerosis, hardening of the large and small arteries of the brain. And then in fact, this cognitive loss associated with specific neuropathologies was to a large extent driven by vascular pathology. So that’s my nun study.
And you can see that I forgot to tell you about this guy, and Lewy bodies are really important too. And you’d see more of Lewy bodies. And we don’t often talk about Lewy, which is interesting. And I think it’s because he doesn’t have a mo. And I think that we’ve just, he didn’t have that magnificent mo, so these Lewy bodies … Yeah, we could draw one in for him, but he’s very mo-less, in all the pictures. Okay. The other thing that really argues … Yes, very, very mo-less.
The other thing that really argues that these vascular risk factors are important is that whilst we talk about the huge problem that dementia in the world is going to cause, is causing now, we know that dementia incidence, not prevalence, prevalence is skyrocketing, incidence is declining. So I’ll just say that again, dementia incidence is declining globally. Some studies have found about a 26% drop in dementia over the last decade with more pronounced declines in women, so it’s great news. And it may be because these sex specific differences are starting to emerge.
We now know that women who’ve got cardiovascular risk factors are one and a half times more likely to get Alzheimer’s disease, not so much vascular cognitive impairment and dementia. Men tend to get that. There’s an average decrease of 13% per decade over the last 30 years, and people in more recent birth cohorts have a lower risk of developing dementia at any given age compared to previous generations. So this is fabulous news. This is because of all the work that you are doing and we’re doing globally. And you can see that this has been shown in studies in mainly high and middle income countries, but in several countries in Europe, in the UK, in the US, in Canada, and also in Korea, Japan, and not so much in China. Because China, there’s still a big problem with vascular risk factors. So it’s good news that we can actually treat or maybe prevent.
This paper also came out in the Lancet Public Health again from the Lancet Commission Group. And it was looking at pooled data and meta-analyses of dementia incidence. And they showed that changes in dementia prevalence and incidence had been fairly well documented. And they looked at population attributable fractions of risk, which is what those Lancet commission curves were, the PAFs of different risk factors. They found that overall lifestyle interventions such as compulsory education and reducing rates of smoking probably were reducing incidence in the world. They hypothesised that, obviously it’s not causal.
So what’s come up more recently though, and there’s a number of studies. So we’ve known this for 20 years, that vascular risk factors, but we’re now seeing in the pathology, again, my ROSMAP study, where this time there were 1,500 people that had donated their brains, and they looked at trends across birth epoch. So this is starting from a hundred years ago, you were born in 1905 or up to 1930, and they found something that I think is really interesting. They found that in their people, there was no difference in the prevalence of who actually was given a diagnosis of Alzheimer’s disease or who had mean global pathologies, so the Alzheimer’s pathologies were still there, but they found that there was a big reduction in, sorry, I’ll go to this, atherosclerosis and arteriolosclerosis.
So what they found is that the pathologies were, so dementia incidence was declining, Alzheimer’s diagnosis was declining. They still had the same amount of Alzheimer’s pathologies in the brain, but they had less vascular pathologies. So they concluded from this, this is Julie Schneider’s group and David Bennett’s, and he doesn’t want to rock the boat, I don’t think. She said that the time of, improvements in time were probably associated with improved resilience to pathology. That is cognitive resilience, presumably, you’re better at having this in your brain, but you don’t get dementia, but also the vessel pathologies were markedly lower.
I would interpret this, that they didn’t get a diagnosis of dementia because their vessel pathologies were better. And this is from Grodstein from two years ago, three years ago now. Vascular pathologies are declining in brain bank participants. So Marita’s already spoken about this, so very thankfully I won’t need to go into it, but just to iterate, cognitive impairment and dementia are often used differently by members of the community. And I think you all are aware that people come in with different meanings of these terms. ‘Subjective cognitive impairment’ or ‘subjective cognitive complaints’ is the term we use for people who experience cognitive symptoms. So it has no other value. It’s just saying, this is, I’ve got this problem.
But we know now these people were often dismissed, because they’re often women. We know now that people who come in with a subjective cognitive complaint actually are at higher risk of developing cognitive decline. They are experiencing something and noticing something. I think one of the issues is that people who truly do have dementia, in my clinic, probably at least less than 50% think that they have a problem. So when you’d have dementia, insight is affected as well. So it’s a very different thing. These people are noticing the problems. And brain fog absolutely falls into this category, but so does every major life experience. I think that all of us have experienced major life events when we’ve had loss of a partner, child, family member, when we’ve been under extreme stress, sleep deprived, when we’ve been breastfeeding or postpartum, your brain does just not work. And I think that subjective cognitive impairment can have, as Marita said, many, many, many causes.
But ‘mild cognitive impairment’ is a research term. I’m just going to emphasise that. It was a research category that Ron Petersen devised to say, “Well, these are people who are at risk of developing dementia.” We now use it as a diagnosis. I don’t like it as a diagnosis. I’d like to say, what’s wrong with you, that you have depression or that you have sleep impairments. It’s a research category for people with cognitive impairments. It can be used as a diagnosis, it’s just not my thing.
‘Dementia’ is the term we use when people have progressive cognitive impairments that are affecting their ability to function. Most dementia is due to degenerative processes in the brain, and these can cause neurodegeneration. There are some dementias that you can get after getting Korsakoff syndrome or multiple strokes that all happen at once or severe autoimmune cephalitis that have occurred just really in a short space of time, but in general, they’re progressive neurodegenerative processes.
And we detect neurodegeneration mostly on MRI scans in 2026. Certainly CT scans are fine, not everyone can have an MR. And we see lots of things. We see atrophy and we see changes in white matter, which are white matter hyperintensities. The full term is ‘white matter hyperintensities of presumed vascular origin’ because there’s lots of causes for white matter hyperintensities. We see them in MS, but they’re demyelination. We see strokes, we see bleeds. The changes that we see are these vascular changes, or we see atrophy. PET scans, which we can do now, and certainly as specialists, I’m allowed to order up to three in a person’s lifetime, Medicare rebatable PET scans, FDG PET scans, to look for changes if I’m suspecting a diagnosis of Alzheimer’s dementia. So they are great, and they show us the pattern of hypometabolism, the pattern of neurodegeneration.
There are now PET scans, and you will be getting a lot of questions about this, I imagine, that allow us to image amyloid and tau. Tau’s just research, but you can pay for an amyloid scan. So people will come to see you and ask, “Can I detect this brain pathology in life?” unlike the Nun study, and we can, that is about $2,000. So most people don’t want them, but there’s a group of people who are very interested. The big transformation in this space, and again, Marita and I talk about this in the cases, is that we’ve been able to measure brain proteins via a lumbar puncture, via CSF for decades. There’s a lab at the Florey that’s been doing it for decades. But we can measure brain-derived proteins, so from our brain, in just a normal blood test now. This is huge. This is due to big change in single molecule assays, extraordinary ultra, ultra sensitive assays, and it’s really transforming how we think about diagnosis of dementia, but we’ll speak about that next.
So I’m just going to talk a little bit about brain volumes. And again, Maria introduced this, that paper that came out last year that was, “Oh my god, you’ve hit menopause, that’s it. Your brain’s shrunken. It’s a tiny walnut and it’s a disaster.” And as Marita said, it’s not that bad. And I agree that that discussion was excellent. And I read the conversation piece last year, and I think those authors were really going, “Oh my god, I’m walking this back.” Our brains, sadly, well, not sadly, but truly, reach peak volume in the third or fourth decades. That’s in our 20s and our 30s. And they decline after that, which is sad, but so does everything. I mean, our skin gets thinner, we lose disc space, we get shorter. It doesn’t mean that we’re losing brain cells. It doesn’t mean that we’re losing brain cells.
There’s been a number of studies looking at brain volume and cognition, a lot of them from the UK biobank. So again, a really fantastic study done in the UK, half a million people, a lot of them with MRI, data linkage, extraordinary, a little biassed in terms of diversity and who’s actually volunteered for this study. And we know that when we look at brain volumes, that yes, that menopause is associated with grey matter decline, but most of them have been done by people who are more interested in the mental health. So the lens has been, let’s look at their mental health issues and let’s see what’s happening with that. Oh, and let’s look at their brains as well. And low and behold, they’ve found that menopause is associated with a decline. But our brains do lose more volume in our 40s, 50s, and 60s than they lost in our 20s and 30s. So it’s not that surprising.
What they’ve shown, and that the spin of this, was that HRT doesn’t help. MHT doesn’t help. So your brain’s going to shrink. It’s going to be a walnut and taking the drugs don’t help, but they don’t also hurt you either. So it’s actually part of our natural history of our brains. It’s not associated with increased risk of dementia. There’s no effect on brain volumes of MHT, HRT, either way. So if women want to take it because it suits them because they’ve got sleep problems, well take it. If we think of the scare about three years ago where they said, “Oh my god, you’ve got an increased risk of dementia because you’re on MHT,’ well, it’s not true.
We know that those midlife cardiovascular risk factors determine our brain health. And when they looked at that and brain volumes, it was the cardiovascular risk factors that were largely determining how quickly you lost your brain volume. Although it feels like you lose your brain sometimes.
There are some data from Australian studies, and I think we often, because of the UK Biobank is so big, 500,000 people, 125,000 women, that we’ve been running, Lorraine Dennerstein’s been running this women’s healthy ageing project from last decade. Cassandra Szoeke has taken it over, and they’ve been looking at, now, small numbers of women who are still in the study who’ve got, with an interest in cognitive profiles and dementia risk. And again, they’ve borne out very similar. So these are Australian women. These are mostly Victorian women. Those people who’ve got impairments and smaller brain volumes, nothing to do with their hormones, it’s to do with their hypertension, their physical inactivity, and their dyslipidaemia. So really important that we treat those.
And again, this was this Zulsdorf study that showed that women have more mental health problems in menopause, and they reduce their grey matter more, but in fact, the HRT isn’t affecting them either way.
The risks. So again, I know I am really banging on about this, but I cannot emphasise how important these risk factors are. Hypertension is arguably the greatest global driver of dementia. So I think that we really need to be, if someone’s hypertensive, and I was interested to hear those renewed, the change from 140 on 90 to maybe 130 on 80, maybe we should be thinking more, we should be more aggressive with our women. I mean, obviously they cause side effects, but the drugs are so great now. Hypertension affects women at all life stages. Their rates of hypertension increase with age and postmenopausal women have the highest rates. In fact, in our 50s is when all of those risk factors come to roost, and they do in men too. So it’s not surprising that the hypertension rates start to bump up. No doubt that the menopause affects it.
I often, when I’m trying to convince someone in clinic to take her anti-hypertensives, I say to them, “You know that if you don’t have blood pressure problems, you’re going to live five years more.” So non-hypertensive women have five years longer lifespans, these are global, these are epidemiological studies, than those with hypertension. It can be controlled. And in most women, it can be controlled very easily with a single therapy. And interestingly, over the pandemic in Canada, they found that there was, because of health anxiety and isolation, that a lot of, there was actually a reduction in risk reduction for women, particularly the antihypertensives, down 20%. And they have shown that in their health data, public health data, there’s been an increase in cardiovascular deaths and hospitalisation. So the drugs really work short term and long term as well to prevent dementia.
We can speak more about obesity and insulin resistance. It’s interesting, we had a dinner last year with Sue Davis, who’s the menopausal guru in Australia. And she was saying that perimenopausal weight gain actually starts five to 10 years prior to menopause, at one kilo a year. So it’s not just over the menopause. The menopause is associated with a distribution in central, to central body fat, which anyone who’s going through this will have experienced, but we also do less. We have a decrease in energy expenditure that’s associated with weight gain. We get insulin resistance. And apart from hypertension, insulin resistance is a real problem. Some people talk about insulin resistance being a profound driver of amyloid pathologies. I think there is good evidence for that. We know that that’s associated with that syndrome X. I don’t think we call that anymore. But this proatherogenic lipid profile, those LDLs are really the baddies, not just for cardiovascular disease, but for our brains.
And we know that while HRT/MHT can help with body fat deposition, it’s not associated with weight loss. So it can redistribute where we put on the weight, but we don’t get weight loss. So it’s not going to actually help on itself. Again, not for or against, just saying that I think there are some people who believe that it’s going to solve all of the problems associated with the menopause. It’s just not.
Sorry, this is a slide from a public lecture I gave. So it is true that LDLs are the baddies again when it comes to our brains with dementia risk. In fact, it’s one of the ones that was added to those curves I showed you before. And during the menopause, our lipid profile changes, as Marita said. The other problem with this abnormal fats and sugars and sleep is that the more obese we are, the more likely we are, sorry, to have sleep apnoea. And menopause is associated with profound sleep disturbance. Don’t forget that some of that might be sleep apnoea. And I think that sleep treatment is a really important thing. I, obviously I run a cognitive clinic or clinics, I’m often referring people for sleep studies. You can do them in the community now. I have a 60% positive hit rate. And we know that in people with stroke, for example, 60% as well have sleep apnoea and they’re fine. They think they’re fine. And these are people who probably need treatment.
So it’s such a silent epidemic and it’s a real issue with the menopause and that they also increase in men as well in their 50s, but definitely in women. So I put this, I took this from the Health Week for Jean Hailes last year just to show how brilliantly … So this is the week that you did, the first week of September. Everything is what we’ve just spoken about: getting checked, taking the lead, making sure that you’ve got the right knowledge, being heart smart, and talking also about pain, which is another unmet need in women, and being kind to your mind. And I haven’t really spoken about mental health, but it’s a massive issue as well. And it is on that curve.
So just to finish with this, because it was a question earlier. So what reduces blood sugar, blood pressure, LDL, obesity, and improves our mood, our sleep, and our longevity? And it’s not HRT, although it can help. And it’s not Sudoku, because all my patients ask me about brain exercises, and because it doesn’t do anything. I have had people who have really demented completing their … I can’t do them, but they can do them, and they’ve got dementia and I don’t, yet.
So it’s exercise, obviously. So let’s talk about brain health and neuroprotective lifestyles at every stage. So I’m going to just talk about physical activity. Because I think that, I’m a big fan of exercise prescriptions. I think they’re the neglected prescription. I think we’re not talking about this because it’s so much else to talk about. There’s so many other things that we need to be discussing, but I think that this is the neglected prescription.
So physical activity for brain health. Physical activity, particularly huff and puff exercise, but resistance as well, is so important. It increases brain-derived neurotrophic factor, which actually does exactly that. It says to the cells, grow. Synapses, do things. It increases VGF, which is a endothelial vascular growth factor. It’s healthy for our blood vessels. It’s the only thing that increases hippocampal volume or neurogenesis in our memory centres in our brain. The only adult behaviour that we know continues to do that. It increases our cerebral blood flow. It reduces our vascular risk factors. We know it’s reduced. It’s associated with reduced cognitive decline. It improves our cognition.
So physical activities and sedentary behaviours, so physical inactivity and sedentary behaviour. So there’s two different things, obviously sitting, lying, sedentary behaviours, they’re bad for the brain. But also not doing any physical activity is bad for the brain. So higher levels of physical activity, lower levels of sedentary behaviours are associated with better global function in older adults.
So this is something that we can say is good for you in midlife because it does help with sleep and it helps with mood as well, but it’s also going to be good for you when you get older. When I look at the effect sizes, I didn’t show a definition of that then, but we know that the effects are greatest for moderate to vigorous physical activity, and time spent active, or total physical activity. That more physical activity, to a point, so ultra marathons are not good for your brain, not good for your heart, not good for your brain, but more physical activity and higher intensity as well. Sadly, for those of us who don’t love HIIT, facts are there, you just got to suck it up and do it, that are most beneficial for global cognitive function. And lifelong physical activity is strongly associated with dementia risk.
Evidence is probably even stronger for women, more for women than for men. And I think that that’s also been neglected. It’s important to do resistance and cardiorespiratory exercise, and it’s good for our heart, our bones, our brain. It’s good for everything. We looked at people after stroke with a variety of tricksy imaging methods, and we showed that physical activity after stroke is associated with better brain connectivity in our attention networks. It also reduces those white matter hyperintensities as well. So you can actually have brain health at any stage. And we did a study because we found that after stroke, particularly, women and men, but particularly women, lost brain volumes at a much higher rate than people who had not had stroke. So we need to be really implementing these strategies at those at risk. Just because you’ve had a heart attack, you wouldn’t say, “Oh, you shouldn’t do any exercise.” I think sometimes with people, we say, “Oh, well, perhaps those things aren’t so important.”
We did this study where we looked at two arms, cardiorespiratory versus a balance and stretching. And we found that whilst there was no difference in brain volume change between exercise groups, their brains shrank at the same rates, those people who were in the cardiorespiratory group had faster speed of processing, their brains worked faster, and they had better global function than those in the balance and stretching. So HIIT does work. A colleague, James Broach, is comparing sedentary people who’ve never exercised middle-aged adults, compared, looking at two different ways of delivering exercise, HIIT and moderate intensity cardiovascular training. And we know that they’re finding similar things as well.
But we also know that less intensive therapies can work, and there’s certainly benefits for a yoga intervention that we’ve seen in stroke survivors. So I think this is the future of brain health. It’s biomarkers, it’s exercise, sorry, if you don’t like it, it is, and advocacy. So I’m thinking that as we’ve heard earlier, that we really need to be thinking about the risk measures that we’re going, and it’s all those things that we’ve discussed, blood pressure and smoking and cardiovascular risk factors and inactivity.
We can measure the brain better now with blood tests and with cognitive tests, as well as with brain imaging, which is my thing. We can assign people into different tiers, if you like. They’re great, they may be at risk or they’re impaired, and then we can actually do targeted prescriptions for brain health optimisation. And some of that will be exercise prescriptions. And when I do public talks, I always end with a few pictures, with a bit of inspo, and these are some people who are marathon runners in their 80s and 90s. I mean, this guy, Ed, did a sub 4 hour marathon at 82. I could not do a sub 4 hour marathon. Take me two days. And this woman’s 90 and she did it in just over seven minutes. I’m a yogi, and so I like to put up pictures. This woman died at 103 and she was the oldest instructor in the world. This guy is 105. This man is doing this at 105, so age is no limit.
So vascular health is brain health, is brain health, is vascular health, for mid to late life. Whilst your vascular risk increases over and after the menopause, the risks can be managed. MHT does not affect your brain health risk either way. It’s good news for those who need it, good news for those who can’t take it or choose not to. Stretching, balance, resistance exercise, yoga and Tai Chi all demonstrate brain benefits. So do what moves you and your patients and consider exercise prescriptions.
And again, and we’ll talk about this a little bit more, we need to rethink our models of care, what’s best suited to our medical systems and communities and cultures. I’d like you all to be brain health champions and ambassadors, and really looking forward to the launch of the women’s brain care clinics at Jean Hailes.
And this is a picture from me. I finished my yoga teacher training last year, and there we are in front of our mandala. I think we should all get up and move now. Thank you.
End of transcript
Presenter
Professor Amy Brodtmann MBBS, FRACP, PhD, FANZAN
- Professor, School of Translational Medicine, Monash University
- Professor, Cognitive Health Initiative, Monash University
- Cognitive Neurology Clinical Lead, Royal Melbourne Hospital
- Director, Eastern Cognitive Disorders Clinic
- Honorary Professor, Florey Institute of Neuroscience and Mental Health
Slides for download
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Download A Primer from Pathologies to Protection slidesViewPDF • 5 MB
Webinar chapters
- 00:00 – Introduction, background & acknowledgement of country
- 02:00 – Why dementia matters: prevalence, burden & gender differences
- 04:00 – Historical foundations of dementia pathology
- 06:00 -The amyloid hypothesis and its limitations
- 08:00 – Broadening the model: inflammation, synapses & metabolism
- 10:00 – Dementia risk factors across the life course
- 12:00 – Midlife risks: vascular health, hearing loss & social isolation
- 14:00 – Hypertension, stroke & vascular contributions to dementia
- 16:00 – The Nun Study: mixed pathologies and vascular impact
- 18:30 – Declining dementia incidence and population trends
- 21:00 – Changing brain pathology across generations
- 23:30 – Cognitive complaints, MCI & defining dementia
- 26:00 – Imaging, biomarkers & modern dementia diagnosis
- 28:00 – Menopause, brain volume & hormone therapy myths
- 31:30 – Key modifiable risks: blood pressure, lipids & insulin resistance
- 35:30 – Sleep, obesity & cardiometabolic health
- 37:30 – Exercise as a neuroprotective intervention
- 41:30 – Evidence for physical activity across the lifespan
- 44:00 – Key messages & closing remarks
Continuing Professional Development (CPD) information
- Identify the role of vascular risk factors in the development of dementia.
- Describe how dementia involves multiple pathologies
- Identify key modifiable risk factors across the lifespan that influence dementia risk.
- Outline the impact of midlife health behaviours on late-life cognitive outcomes.
- Describe the benefits of physical activity for brain health and cognitive function.
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Acknowledgment of Country
This webinar was filmed on the traditional lands of the Wurundjeri and Gadigal peoples. Jean Hailes for Women’s Health acknowledges the Traditional Owners of Country throughout Australia and recognises their continuing connection to land, waters and culture. We pay respect to Elders past and present.
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