Effective Treatments and Prevention of Alzheimer’s Disease: The Time is Now – Research on Aging

the Sam Andros Stein Institute for research on Aging is committed to advancing lifelong health and well-being through research professional training patient care and community service as a nonprofit organization at the University of California San Diego School of Medicine our research and educational outreach activities are made possible by the generosity of private donors it is our vision that successful aging will be an achievable goal for everyone to learn more please visit our website at aging dot UCSD edu well good evening everyone and welcome to the UC San Diego center for healthy aging monthly public lecture for those of you I haven't had the chance to meet yet my name is Danielle Glorioso and I'm the executive director for the Center for healthy aging and the Stein Institute for Research on Aging I'm really delighted that all of you could skip the debate tonight and join us here this amazing talk I'm just so delighted to see such a lovely turnout tonight for those of you who are new to us the Center for healthy aging focuses on advancing lifelong health and well-being through innovative research training and community outreach this public lecture series is just one example of our community outreach programs many of you know that we've been offering this program for over 30 years now free to the public with the thought that we want to connect the community with exciting advances that are happening in research and aging here at UC San Diego so as I mentioned this public lecture series is free to the public and is supported entirely through donations so I'd like to thank all of you for your continued support through the years because we would not be able to support these wonderful programs without your help if you'd like to learn more about all the exciting work we're doing here you can find us at aging UCSD edu I'm just delighted to introduce our speaker tonight dr. Howard Feldman he's a new director of the Alzheimer's disease cooperative study here at UC San Diego and he also serves as Dean for the Alzheimer's and related neurogenic degenerative research here at UC San Diego School of Medicine his arrival coincides with the launch of the University of California's program to accelerate the most promising Alzheimer's disease research into early proof-of-concept clinical trials so this really is an exciting time for research here at UC San Diego in 2007 the journal Lancet neurology called him the master of dementia what a title and in 2014 Thomas voyeurs named Feldman among the world's most influential scientific minds boy are we lucky to have him here tonight he's also most highly cited researchers in neuro science and behavior please join me in welcoming dr. Howard Feldman thank you for the very kind introduction the accolades are to the extreme I'm unworthy of them thank you so it is my pleasure to be here and to speak to you this evening okay so the title of tonight's talk is finding effective treatments and prevention of Alzheimer's disease the time is now how many of you have a vested interest in this problem very good okay so let me then tell you a little bit about my trajectory and how I got here so at least you have a little bit more understanding of this so this is a bi-national story I was recruited to UCSD in April from the University of British Columbia a beautiful campus on point grey in Vancouver I previously had served there for more years than I would care to publicly acknowledge but you see some timelines we created a Center for brain health while I was there you see this beautiful building and if you have really good vision you'll see that there are some cartoons of neurons and synapses modeled after qahal who was a Spanish neuroanatomist and we've embedded those in the walls and as the children go by they tend to say well why do you have octopi on the walls of this building I directed the Alzheimer Clinic when I was at UBC and served in various other administrative functions I also had an opportunity in a very unique turn of events to work at bristol-myers Squibb for three years where I was the therapeutic area head for Neuroscience and led their global global clinical research so this was an opportunity to actually advance Alzheimer therapeutics right at the coalface so very close to where molecules reach humans and potentially become the medicines that we use every day so being a university faculty we never leave home without making disclosures so this is my disclosure of some of the things that I've been involved in outside and within my role at UCSD for your easy reference so have a few goals for tonight's talk so the first is to ask the question and enable your understanding on how we're doing trying to find an effective disease modifying alzheimer's disease treatment and I'd like to take you on this very interesting scientific journey from neuropathology to molecular targets to clinical treatments and I'm going to go all the way back to where dr. Alzheimer first described this disease and how we've approached this and what we've learned along the way I would like you to be up-to-date with understanding what the risk fire factors are for Alzheimer's disease and other dementias and how you might modify your risk factors particularly those that have the potential to delay the onset of dementia and then I put this in a box for you because it's probably the most important one which is to pick up some tips for your own brain health who would not like that pretty good okay so you heard about the Alzheimer disease cooperative study so this is a network that conducts clinical trials in the United States you see it has a lot of different sites some of which are member sites some of which are participating sites and I've come to learn that there have been over 31 completed clinical trials done by this network I would say that this is without exaggeration this is the largest experience of anyone in the world at doing clinical trials and the coordinating Center is here in San Diego so a very remarkable history and it's been at it since 1991 if I put into words what the ADCs does it's a funded network the tests novel treatment for the symptoms of Alzheimer's disease and its Prevention's we test medicines and interventions that are unique and might not be otherwise tested so there are a lot of things that come up that are of interest to the public that may be not to the private sector and those have to have a place to be tested and the ADCs is a place to do that the funding model is largely public it also has some private components so we will collaborate with biotech companies and other partners who have interesting things that they want to test and maybe don't have the resources with which to test them we have the support of the School of Medicine here at UCSD the NIH and as mentioned industry partners so we're gonna start with things that you're probably familiar with as I look around this room I see a fair amount of gray in the audience of course it's easier when you don't have to look in the mirror this is the growth of individuals over the age of 60 looking from 1950 onwards and what the projections look like you can see that there will be an eight times increase in growth within our segment of people over the age of 16 when it comes to the problem of Alzheimer's disease and dementia in 2010 just imagine this at a global level the cost being of care being six hundred and four billion dollars in 2015 the best estimates were that there were 47 million people affected by dementia and Alzheimer's disease by 2050 that number is going to triple to a hundred and forty million people that's like an oh my god moment one new case every four seconds so that's really remarkable that did not escape the attention of our politicians the National Alzheimer's project Act called Napa was formed in 2011 its goals as mandated through Congress were to prevent and effectively treat Alzheimer's disease by 2025 they helped expand research funding to upwards of 1 billion dollars annually now a national project Act for Alzheimer's disease sounds like something that others would do but what really impressed me about this was the accountability that gets tied to the Napa project so the people that are in charge of Napa are called in front of Congress every year and held accountable for the progress that's been made against the goals for Alzheimer's disease so it is a very large initiative President Obama signed into law 350 million new funds each year starting this year and the ni a accordingly has had a quite significant increase in its budget in 2013 I had the privilege of being invited to a g8 summit the global action against dementia its ambitions amongst the g8 countries were to identify a cure disease modifying therapy by 2025 you see a relative synergy in the way that all of these ideas were come together but one of their goals was quite interesting actually it was to increase the number of people in dementia related research studies so outside the door and I will dispatch this part of my responsibilities there's a table of the shyly Marcos Alzheimer Research Center they do lots of trials many and lots of studies many of which involve normal volunteers so please feel free to pick up some pamphlets and they would welcome your interactions with them the World Health Organization led by Margaret Chan said that they broadened their viewpoint so the World Health Organization is a public health organization they say we should improve the quality and availability of care we should seek a cure but we need an urgent investment in primary prevention measures so what an intriguing idea the idea that we might be able to forestall dementia or prevent it and I'll tell you a little bit more about that as we go along here's our progress with therapies so I'm going to tell you a little bit about dr. Alzheimer in 1906 if we fast forward a hundred years we've seen the development of several types of treatment a group of medicines called cholinesterase inhibitors you see three molecules down below they were landmark insofar as we'd never had a medicine before that could help any aspect of cognition reliably and these showed with some measure of reliability that they helped some but not all people we of course became very greedy we wanted if something's going to work we wanted bigger effects sizes we wanted better impact of the therapy so that led us on in 2003 there was approval of a medicine called memantine which worked on a different receptor in the brain the NMDA receptor and an uncompetitive receptor antagonists and we've been going through a drought despite monies being spent finding treatments since 2004 there's been really no success and there's been a certain resignation and discourage discouraged feeling in the field that this may be harder than we thought it was going to be there have been 2,000 clinical trials in the last 20 years so you can see that there's been a problem with our success rate and it leads us to go back to fundamentals and asked what we're doing right and what we're doing wrong in our concept of this disease so the journey takes us back to where dr. Alzheimer starts it takes us through neurological pathology which is to say when the brain is donated at the end of life and we look down the microscope what are the features that we see and how have we come to understand the molecular pathology so what are the proteins in the brain that are miss folding miss aggregating and being mishandled so dr. Alzheimer was called to see a patient agus D eventually she was mitad to the hospital she was described to have had a rapidly worsening memory I should say that she was only 56 years old so it's quite perplexing to see such a young woman with a rapidly worsening memory she couldn't find her way around the house without getting lost when she was brought in the hospital she was entirely perplexed she was disoriented to time and to place she had trouble understanding those around her and she made errors in her language she thought that her husband was cheating on her and had considerable jealousy she was yelling that she was about to be murdered despite all of that her primary neurological function her gait her use of her limbs was entirely normal and she had a pretty aggressive disease she died after four and a half years they got to examine her brain at the end of her life and these are some of the original histologic sections so this section in here is actually from dr. Alzheimer's presentation in 1906 that's pretty cool and he described these round things I think at the time he probably wasn't quite sure what they were they've subsequently we've determined that they're called Sanel neritic plaques their little calcified collections of proteinaceous material with the core of amyloid beta so we now know what these are this is called a tangle so if you imagine that a nerve cell is normally shaped like a pyramid and imagine if the pyramid lost its skeleton and just collapsed in on itself so tangles and he also described some changes in the blood vessels he thought it was a vascular disease we discounted that for several decades we're coming back to it for reasons that I'll explain so all of these findings were immutable and it led us to consider in hindsight as I was thinking about this it reminded me of Sutton's law does anyone remember Sutton's law yeah so Willie Sutton was a bank robber and they said well why do you rob banks he said well of course I rob banks that's where all the money is so they applied the same kind of logic to this problem and said well the money must be here and it must be here and it must be here so why don't we see if we can remove the offending pathology let's figure it out so I first want to tell you about the part of this story that's called cinematic plaques and amyloid and we've come now to understand that this is one of the earliest molecular signatures of this disease and people have thought this was really the rosetta stone of this disease and credit should be liberally given to dr. george glenn ER pathologist here at UCSD in 1984 he decoded this protein and he described the amyloid beta protein and its relationship to Alzheimer's disease so that was a pretty proud day for UCSD I would say it's been a fairly enduring contribution and we've got better pictures though of what these amyloid plaques look like and we've learned a lot more about the these amyloid plaques look at this ring of purple cells these are inflammatory cells they're called microglia and it turns out there like a scavenging army so as soon as you put amyloid beta into the brain you get a descent of these microglia that provide a ring as if they want to stop the amyloid from growing they want to surround it and remove it we've been trying to think about how how we can advance anti-inflammatory medicines on the grounds that maybe it's harmful although there's still equipoise I don't think we really know whether this activity is harmful or helpful and this is just to show some of the immuno reactivity of the amyloid it really does trigger the immune system into a we've learned a lot about the way that amyloid is metabolized so this is a big protein this is about 700 amino acids it's called the amyloid precursor protein it's the parent protein from which this amyloid beta fragment which is only 40 amino acids 42 amino acids gets cleaved so there's a set of scissors that cleave the various fragments this is the moiety that's been felt to be toxic if you cleave down this pathway you get fragments of amyloid that don't seem to be toxic so a simple solution to this might be programmed to the left turn off to the right so that's taken us 20 years to try that approach without yet achieving success so the story gets a little bit more complicated so as you cleave amyloid beta it turns out it's very hard to work with it's incredibly sticky and if it starts in monomeric form and then it forms into oolagah Murs all grammars are soluble species maybe up to ten or twelve amino acids or ten or twelve clumps of beta amyloid that stick together and then eventually it goes into these things called proto fibrils so now it acquires a beta crystalline structure so now it gets firm it's got a beta pleated sheet structure and here we have the microglia just hovering around so one of the problems with Alzheimer's disease is that we couldn't tell if there was amyloid beta in the brain and in the spinal fluid or not and one of the most remarkable progress is that's been made was in 2011 or somewhere between 20 2009 2011 we actually began to see amyloid in the living brain so imagine for a moment how privileged we are through scientific discovery to see colors these hot colors represent aggregated amyloid data in the brain that makes it much easier before we would only infer in fact the worst of it is we'd have to wait for people to pass away and then have a brain donation then look at the brain and post-mortem and that was the only way we could be sure that amyloid data was in the brain now we get to see it with PET scans this is a procedure we have here in San Diego and many other centers where we can look for amyloid beta in the brain we also can do lumbar punctures which involves passing a needle in between the bones and the spine taking a sample of fluid and looking for the footprint of amyloid and this is how cool this is a moment for how cool is this and just pardon the jargon but I just can't restrain myself so this is a normal individual so this was a research study that took a lot of imagination they said we're going to try and find individuals that are within a year of their presumed death so people with advanced Alzheimer's disease people that were donating their brain that had other problems and they were able to harvest quite a lot of brains this one without any warm colors in it so the warm colors are the yellows and the Reds looks pretty normal even without knowing anything about PET scans you probably nod your head yeah that looks pretty good I don't see much yellow or red there and this is what the brain looks like these are the amyloid plaques right so I think I could probably arm twist you into saying oh I don't really see any immunohistochemistry of amyloid that's normal this one is on the margin of turning positive with these findings and you see what the plaque score looks like in these images and this one I don't think there would be any doubt that this is a positive scan and these correlations are incredibly strong 96% agreement between the clinical classification and the imaging findings between the pet and the neuropathology so really an unprecedented viewpoint into what this might look like dr. Glenn errs ascertain meant of amyloid led to the amyloid hypothesis the idea was if we could clear amyloid from the brain we'd get rid of all those plaques how great would that be we cure the disease and we could move on to the next disease now what's the evidence for this so amyloid is invariable it's early and it's seminal we've come to learn that it occurs probably 10 to 20 years before symptoms begin so we actually know that it occurs very early you can't actually have Alzheimer's disease without the amyloid appa the– you could have dementia without amyloid appa the– but you can't have Alzheimer's disease without amyloid appa the– by definition the genetics are remarkable now there are these rare forms of Alzheimer's disease that are genetic and by genetic I'm referring to an autosomal dominant pattern of inheritance which means that it moves with a 50% risk for a generation to generation it only occurs in point three percent of the time so it's very rare but it's very important because if you have a mutation of that precursor protein a P P or in any of the cleavage enzymes called pre Sanel and one or pre-civil and two you will invariably get Alzheimer's disease and you will invariably have abnormal amyloid beta so there's clearly a smoking gun next to the genetic forms of Alzheimer's but what was very exciting was out of a study in Iceland they found a mutation that protected against Alzheimer's disease so when individuals had this rather rare change in their DNA they were protected against Alzheimer's disease so a mutation causing the disease and a different mutation protecting against the disease so the genetics look like there's something in there the we have to pay attention to in down syndrome there's an extra copy of the a PP gene there are three copies and its associated invariably with amyloid Appa the–and what looks like Alzheimer's disease and we've been able to through the remarkable work in the mouse and rat labs take these mutations and we can insert them into the DNA of a young mouse we breed them so mice and rats have these abnormalities and let me show you some of the remarkable things that we can do with that so by now you're getting used to looking at amyloid beta so this is the hippocampus of the brain this is the seat of memory in the brain and look at the density of this what do you think of that pretty remarkable this is a mouse that had this path all it would get this pathology but they're immunized with amyloid beta so someone had this very clever idea Dale shank had this very clever idea I said I wonder what would happen if I immunized this mouse who was gonna get Alzheimer's disease with the protein itself give it an adjuvant put it in the mouse and lo and behold that was a result I said oh that's easy give him the Nobel Prize we're done with this so that was pretty good and then this was the result so these are the mice making errors when they're given the mutation and this was their error rate after they were given the vaccine so we could not wait to get this into into people because we were thinking this is just too cool to believe so off we went to people and in fact this was the mouse unvaccinated this is the mouse vaccinated this is the human unvaccinated not so good this is the human vaccinated we did it the only problem was the humans didn't get so they looked like they still had the disease so that was a problem because we thought this was going to solve the problem and actually it didn't and not only that telling us that if we didn't already know mice and men are not exactly the same the human immune system didn't like this not one little bit and you see I'm sorry and you see this blood vessel with a lot of red in it and a lot of inflammatory cells there was an autoimmune disease that got created by using this vaccine so back to the drawing boards we had to go and someone came up with another approach saying rather than actively immunize maybe we should just produce antibodies against amyloid beta and infuse them and in fact that looked pretty good so here's the amyloid positive and here's after treatment almost better right so these are all real time things that are happening and everyone is trying to absorb them and process them into okay what do we do with this now and then what do we do with it now so this might be if you're an investment banker this might be your money slide and there's probably about five billion dollars worth of research studies and you can tell it's not going to be good because I can summarize five billion dollars in one slide except for the bottom entry here which I'll tell you about so this has gotten to phase three trials so these are potentially registration 'el trials bapin uzum absolon is the map which is currently in the field being tested as a preventive monoclonal antibody against amyloid IVIG so intravenous gamma globulin Ganton area map cran AZ map you'll notice the common factor here is you Maps you Maps or monoclonal antibodies against amyloid so that was the way they were built to recognize amyloid and to remove it from the brain so just when we were about to turn the page and say five billion dollars cannot all be wrong a ray of light finally a positive trial so let's spend a moment looking at that so here's what placebo looked like so this is called ad you can you man this is a randomized clinical trial that we're currently recruiting for here it's not an ADC s trial but it's one being sponsored by Biogen what impressed me about the these data are here's the average of persons treated with placebo and you would say doesn't really look like there's been much benefit so that looks about the same here's their three milligram per kilogram dose so decisively less visual representation of amyloid here's six milligrams and here's ten milligrams and this is the clinical information so it looks like there's a dose-response relationship so the first ray of hope now the problem is was this an artifact of a small sample is it real can we believe it what to do next and they're now invested in a very large program of research so for those that are interested I'd you can have is worth attention and this made the the very prestigious journal called nature which is as high up the scientific tree as one and ends up going so that's where we've come to on amyloid except for a few other things and I apologize in advance this may be a little sobering so we now know that amyloid builds up as I mentioned within this yellow space 10 to 20 years before people get symptoms now this is the bad news amyloid positivity so not bad if you're 50 years old 1% 16 not so good 11% 70 even less good 23% 80 34% 95th be percent on average 24% of individuals over the age of 50 are amyloid positive now we need to better understand what that means will everyone who's amyloid positive eventually get Alzheimer's disease will apportion get alzheimer's disease many unanswered questions only we are now doing very large-scale studies trying to understand what the significance of being amyloid positive is now with the progress being very slow along the amyloid front someone turned the question to dr. Alzheimer's second pathology which were the tangle proteins and tau pathology and said well maybe we got the rosetta stone wrong maybe tells the rosetta stone and maybe it's the main event in Alzheimer's disease so get the brain be rid of tau that will help us so what does tau actually do I explained to you that it's kind of helps those pyramidal neurons maintain their structure prevents them from falling in on themselves so tau is a binding protein it stabilizes these pathways this is where the nutrition of your brain cells actually works so all of the nutrition that feeds nerve cells travels through these so called microtubules and if you something happens to your tell these things end up dissolving and they form into a game aggregates a game with some crystalline structure they again form into these oolagah murmurs and then in to crystalline structure so in some ways there's some similarities between the tau protein and the amyloid protein at least insofar as these end up in neurofibrillary tangles now unlike amyloid which does not have a close relationship to clinical symptoms so when I'm evaluating a person and they have memory impairment it's very hard to relate that to their amyloid state by contrast tau abnormalities does relate to their clinicals more often and we there's a fairly predictable pattern of the way Tao builds in the brain I won't trouble you with all the details only to say that we've known this from brac staging of neuropathology but again here's some very exciting PET scanning so this is now a ligand that ties to the tau protein and to tangles so aggregates of tau protein and so again here's normal here's normal here starts to be abnormal so this is now getting to be mildly cognitively impaired so that's abnormal and it turns out that as the pathology exits the hippocampus and moves into the temporal cortex that corresponds quite well to symptoms developing and then here's full-blown Alzheimer's disease so now we have these two molecular signatures for Alzheimer's where we look at the regions of the brain we can begin to understand the sequence so again how cool is that now imagine for a moment that it's not amyloid but tau that's at the center of this it does tie to a lot of things there's tau pathology associated with Parkinson's disease and multiple systems atrophy there's tau protein at the heart of this disorder called CTE or chronic traumatic encephalopathy I've noticed Americans like this game called football we're gonna come to understand that it does have some consequence in relationship to risk Huntington's and epilepsy have some tie-in to tell and tell of course as a relationship that dr. Alzheimer described to Alzheimer's disease so tau turns out to be pretty darn important for a lot of the neurodegenerative pathway now it's also a reminder that the brain is complicated if we needed a reminder this is a reminder that it may not be one thing and this just tells us some of the interrelationships and maybe by studying Alzheimer's disease in a silo rather than studying Parkinson's disease Huntington's CTE frontotemporal dementia maybe we've been doing ourselves a disservice so if you go to meetings you may go to frontotemporal dementia meetings you don't go to the Alzheimer conference you go to the Alzheimer conference you don't really know what's happening in the world of Parkinson's disease so one might argue that if we're ever gonna get a hold of these disorders we're gonna have to think more broadly so this is our success map at trying to target tau treatments so red means we've tried without success brown means they're still in development and you can see that our scorecard again here looks modest at best the only thing we can say is that we're still out there trying so I then posed a question so well one way to understand this is to think about metaphors so I'm thinking about this and then one day it comes to me I said maybe these lesions that dr. Alzheimer described or actually just tombstones so I'm thinking what might that mean and then I come up with this idea it said when you think about it if you went into the graveyard and you took all the tombstones out actually nobody would be any the better for it so if tangles and plaques are simply tombstones of neuro degeneration but not the active lesions we may be going down the wrong way so we have to think beyond plaque and tangle and I want to show you some evidence of what the aging brain looks like so one of the relationships that turns out to be very important is stroke in the brain now stroke comes in various flavors and descriptions stroke can be incidental a bump in the night a small change in function it can be very eloquent where something very and devastating happens and it may be seen only when you do imaging of the brain now if you have some Alzheimer disease lesions plaques and tangles plus you have stroke in the brain it increases your risk of dementia by 20 times so that's not a chance affair that suggests that there's something else when you have multiple pathologies it seems like there's an incremental effect something bad is happening furthermore some of our sanctity and sense of well-being about our diagnostic acumen and this disease comes from well-characterized recent case material so imagine you get the world's best centers to recruit individuals that are said to have Alzheimer's disease and then they do brain donation the end of life they look at their brain and this is not a huge sample but it's a representative sample I think there's something like 22 persons in this only 14% of the people had so low Alzheimer pathology the rest had other protein aapa thiis so say nucleon pathology associated with Parkinson's and Lewy body 44% of people had those markers hippocampal sclerosis with a different protein appa the– 40% vascular pathology 22% and a different kind of pathology called grain disease with another percent so you see it's the rule and if you think about it the aging brain is a very benevolent host it acquires all kinds of things and sadly for us the presence of one pathology does not protect against another so rather the brain accepts them all and they are interactive not only that but if we send people for MRI scans we can't differentiate coincident pathology and our neuro pathologist typically looks at us and says well you guys just aren't very good clinically you should be able to tell this but the truth is that it doesn't express itself clinically it's in the brain it's probably relevant but it's not easy to identify now beyond that I told you about Auguste Dee she was 56 years old and her brain looked relatively pristine for Alzheimer pathology but look at this excellent work of Pete Nelson from studies and Aging in the University of Kentucky where they did the nun studies by the way and look very carefully at this I stared at this for a few hours the other day trying to understand what's this graph actually telling us so what it tells us is that there's quite a big ascent in prevalence of dementia but it also tells us that the yellow space when you're above 80 begins to open up and that's brain arteriosclerosis so it's not that important brain arteriosclerosis or a big problem when you're down at 60 but it does or even doesn't even seem to be a problem till you're 70 and then it suddenly it opens up now it's a problem and you look at lacunar infarcts again a bit of a problem but when you get above 80 starts to be a bigger problem hippocampal sclerosis and in fact if anything the red looks like it's trending to be stable or down so it actually looks like Alzheimer's may be less prominent as a pathology if you have the good fortune to live over the age of 80 and it tends to be other things and then he describes something called primary age-related telepathy and you see it opening up at 80 this is primarily a tau solo pathology so you see that if we did all our trials and we called everything Alzheimer's disease we'd have problems because actually what's underneath it is quite different across the continuum of age and here's just an example of some of these late life things I'm not going to go into detail about it but only to say that there's a whole variety of things that will happen and he's come up with the acronym karts or cerebral age-related tdp-43 in sclerosis that's a bit of a mouthful I'm not sure that name will survive but I think it makes the point that there are other pathologies that are very important now I know the reason you've come here this evening is to be like this pole vaulter or maybe not so what are they let's talk about prevention and think about what that actually means so in 1997 a statistical epidemiologist did some modeling and he modeled out over a period of four decades and he came up with this most remarkable conclusion he began to model and say if we could delay the onset of Alzheimer's disease not at all we'd be on this great ski slope if we could delay by half a year we'd be on this crimson ski slope if we could delay by one year we'd be orange if we delayed by two years and if we delayed in yellow by five years we could cut the prevalence of this disease by 50% over four decades how remarkable is that so we have our marching orders if we're thinking about this as a public health problem we're thinking about so what can we actually do to delay the onset of this disease by six months one year and so on now what's not said here and what you have to say what you have to understand is the idea that implicit in this is that because so many older people are affected people will die of other reasons but I think when given the choice you'd probably prefer to die of other reasons and not to lose your cognitive function or at least you probably wouldn't be here if you're worried about not worried about losing your cognitive function so that's really those are our marching orders and in all the national plans when they talk about preventing and delaying it's all about this model it's all about if we could achieve and as we go through these things I want you to think about what the implications might be so risk factors for dementia so these are lifetime trajectory things so these are the risk factors and what's really interesting about this graph is that some of these things begin quite early in life so as I like to tell people choose your parents wisely because they're the ones that are going to give you your genes and you can see that if you get born with particular genes for Alzheimer's disease that's going to be very important but there are risk factors diet alcohol diabetes depression and particularly the stroke risk factors are very important hypertension obesity smoking cholesterol atrial fibrillation and that will culminate in late life problems but it's not all about risk factors it's also about protective factors so good education and lifelong learning representing something that one can participate in physical activity diet cognitive and social activity potentially being protective and trying to optimize your brain reserve your cognitive reserve now I want to apply some science to this because there's a lot sad that isn't scientific about this so let's go through a little bit of this so my colleague Mia Kitty Pelt Oh in Stockholm came up with a risk calculator so you may all do a mental risk calculator of your own risk the way it works is you put your age here you notice my advice is don't bother living till 85 not so great you start with a 32% risk but anyways you have good fortune so you get a score based on age you then look at family history your risk doubles for each first-degree relative so this gives you a percent then you double it or quadruple it or one time at to get your next risk and then you apply vascular risk factors and you double it or quadruple it that gives you a vascular score and then you multiply your overall risk there is an example if you're 70 and your mother had Alzheimer's disease and you have hypertension that'll give you a 40% risk so pretty darn important and give you some idea that you better take care of those vascular risk factors now these are some data that indicate these are from Vladimir hudgens key in London Ontario says look the trend for stroke is falling and look at that it almost looks like the trend for dementia may be trending down also so maybe there's something important here at midlife and things that we can do what about physical activity and aerobic training so this is a very interesting study here was a randomized clinical trial of physical activity versus usual care so stretching or other things and the idea was that people would moderately intensively walk 50 minutes three times a week they would have a trainer they would have a diary they would be adherent they would do it at home and they would have support between visits so a whole infrastructure to support them but what was remarkable was not only that people did better at six months but they actually did better well after the intervention ended at six months and when it was measured at 18 months so as almost as if something happened to change health practice and lifestyle that sustained itself to benefit in the longer term now this was small improvement in cognition without an improvement in quality of life but that's not so bad for three times a week 50 minutes of activity unless you really don't like activity looks like a good investment we are doing a trial through the ADCs called the exert trial this is with 300 individuals who haven't been regularly exercising but are in good health turns out the bad news on this one is if you're already exercising like a fiend this isn't going to help you you've already extracted the benefit from that one but if you've not been exercising and you're in good health this is worth doing and again I emphasize the idea that having a trainer is a part of this so we had an experience where I got called to a donor who wanted to invest in a trial like this he said how it is so the thing I don't understand is who's gonna pick up the infrastructure cost if the trial is positive and in this program I'm very excited because we got the YMCA across the United States as our partner so this is going to be done within the YMCA's across the country and what's really cool about that is that it allows a pathway for implementation in the future so it's not just a research study that's going to stop in the research lab it's a research study that has the possibility of becoming a program sponsored by the YMCA it's 30 minutes to a target heart rate of 70 to 80 percent ten minutes warm up five minutes of cool-down four times a week two sessions led by a trainer and the comparison is stretching balance and range of motion the problem with this a little bit is that my colleagues that design this trial said well you know mate what if stretching works it's the comparator group and if it does work it's gonna lessen the benefits of active intervention so one of the things we're doing is having a usual care arm here of individuals who meet all the entry criteria but are not going to have either stretching or aerobic training and what I love about this study is its potential for community implementation now can you train your brain so this is cognitive training versus cognitive activity it's an interesting study 2,700 people so a very wealth sized trial with the idea that we aim to try and intervene to train reasoning memory processing speed an intervention given over five to six weeks in sixty to seventy-five minute sessions boosters I love this right now you go and you get a little booster train up at 11 and 15 months and post-training there's improvement with each intervention and reasoning memory and processing speed for up to 5 years so that's pretty good people self-report that they think they're functioning better in their everyday lives when objective measures are done the neuropsychologist can't determine any advantage of the intervention so it's kind of interesting people seem to feel better feel that they're doing better in their lives but it's not measurable and unfortunately in this study there was no difference in dementia incidents over the 5 years so a helpful intervention didn't quite get to where we needed it to be now this is the next generation of prevention trials which is to say okay why don't we put everything together so this one got a lot of play it's called the finger study it was done in Finland and Scandinavia so this was a two year double-blind randomized trial the interventions were diet so optimizing your diet if you needed to lose weight putting you on a diet that would help you lose weight relatively low carbohydrate 10% carbohydrate relatively limited fat exercise cognitive training and vascular risk monitoring so all the elements putting them all together and they took individuals with high KD scores so those that scoring of dementia risk they did yet to score at least a six on that and your cognition had to be at or slightly lower than expected and they were able to get a benefit on neuropsychological test a small effect size but encouraging nevertheless and you see the separations so one thing it didn't do is that it didn't make your memory better but I think this is why people feel that the every day function is better it relates to this thing called executive function so that's your ability to hold things in mind to be aware of things going on around you to plan to execute the things that you want to do and I think consistently on a lot of these interventional trials the benefits come on executive functioning more so than on a pure memory function and I think that's just mobilizing your inherent capabilities okay so if you've been having a snooze I need you to wake up now because this is what you need to take home today so the aging brain is the host to multiple neuropathology and more than that there's a critical interaction between degenerative vascular and other mechanisms which culminate in cognitive impairment and dementia I think it's important to understand that dementia is a syndrome Alzheimer's disease which I've shown you this evening is a very important single most important cause but late life were coming to learn may have less Alzheimer disease pathology and there may be other multiple pathologies if we lump it all together we may never make progress so that's for us as researchers very important I think it also makes it unlikely that we're gonna find a single panacea a single bullet I think it's too complicated for that I think it's gonna require a much more of what we might refer to as a precision medicine approach we may need to take into account vascular we may need to take into account evidence of amyloid appa the– tau up at the TDP appa the– i imagine that we're gonna be if we fast forward five or ten years we're gonna be describing persons unique protein AAPA thiis and then what's needed to treat them nevertheless while all of that work continues to run in the background I hope that I've given you some reason to believe that risk factors can be appreciated can be modified and while the effect sizes are small they're not inconsiderable and maybe by the time we put all those multimodal risk factors together we will achieve a six-month one-year delay in onset of dementia so what else but to quote a Canadian philosopher at the end of this talk so they asked Wayne Gretzky about how you play hockey and he says you have to skate to where the puck is going to be not where the puck is so we bear that in mind so I thank you for your attention [Applause] you


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