Tomorrow’s Breakthroughs Today: Dr. David Holtzman

good evening everyone and welcome to the first Palm Beach science series of the new season uh somebody said to me it's like opening night here right it's Thanksgiving week it's the Monday night uh we're all together um for those who do not know me I am Mark roithmer I have the privilege and honor of serving as the CEO of the Alzheimer's drug Discovery Foundation it is wonderful because we have both um faces that we've had before and new faces notice I didn't use that three letter word beginning with an O and D it's uh so it's great to have some new friends in front as well as friends as we've seen at the series before um as always we will start this with a big thank you to Heidi and Tom McWilliams yeah Tom who serves on our board as the co-vice chair of the overall board and chair of our mission related investment committee and Heidi who is co-chair of all things Palm Beach but it was really Heidi's Vision over a little two years ago let's bring the science to Palm Beach and how right she was so Heidi we are indebted to your vision thank you we have a couple of other co-chairs here with us from our board of directors Ms Nancy Goods Nancy yeah uh who started our Palm Beach Hope on the horizon event going on six years Nancy he's having who's counting right uh which which is great and also with us tonight is another co-chair but she's not going to be co-chair of the event this year because we're honoring her this year is Ms Bonnie Lautenberg and that event start taking place March 15th and I know we all love Bonnie the other co-chair here for us in Palm Beach is Judy Lauder uh and that brings me to the family lawyer about 25 years ago Leonard and Ronald Lauder at the uh at the pushing of their mother Este co-founded the Alzheimer's drug Discovery Foundation based on three principles one it would only fund translational science what does that mean and those of you who've been with us before know how do you go from bench to bedside how do you go from a good idea in a lab and make sure it's helping and taking care of people number one number two the organization would not make grants we would not give out grants we would make investments so the money from the foundation that was going to be given out there would be a contract whether that was with an academic or whether that was with a biotech and if that institution saw any return on investment a portion of that comes back to the addf which we put right back into the science it's called Venture philanthropy and then the last principle that the the water family had was they would partner with anyone to get this done we have an office of about 28 people 14 are scientists 14 are not scientists it was to say to other philanthropists come join us in this journey in this fight for Alzheimer's we have the scientists we want to work together and I I point that out specifically because those of you who've been with us before you've seen this happen people like Bill Gates people like Jeff Bezos people like MacKenzie Scott have partnered with us now on this Journey the other piece that's important with the Lauder family is the loader family takes care of all of the expenses for the Alzheimer's drug Discovery foundation so that anybody who wrote a check to be here tonight every cent of every nickel of every dime of every dollar goes straight to the scientists and the science on the front lines right and we that's a debt of gratitude we owe to the Lauder family for that which gets me to the science at the very beginning at the very beginning of the addf in 25 almost 25 years later we fund three things in science we fund prevention we fund biomarkers and we fund Therapeutics and just to give you a sense of that we now know on this Diagnostics and biomarkers there's a blood test you could take tomorrow that can be predictive of whether or not you're going to get Alzheimer's we also know that with Alzheimer's it's can predict it 20 to 30 years before symptoms ever take hold and we also know those of you who met Dr MIA kivapelto last year you heard her say in these very rooms that 40 percent of dementia up to 40 percent of men can be prevented we can push it out through different Lifestyle Changes the thing that you're going to hear more and more about literally next week in the coming weeks there are now Therapeutics for the first time in over 20 years that are coming to Market that can do something about it so this whole thing of you can learn that this may be in your life well in advance you can do things preventively to take care of it and there's a whole Cadre of Therapeutics that are literally on the horizon and you're going to hear about that today but you're not going to hear about that from me you're going to hear from two leading experts who we have with us today I'm going to introduce the first 25 years ago when the lawyers started the addf there was a wonderful gerontologist who happened to be a scientist at an MD that they in the family worked with by the name of Dr Howard Philip and uh Howard is one of the leading experts in the world on Alzheimer's in fact he's been doing this so long that at the beginning they called it senility right Howard and now they call it Alzheimer's um the waters went to Howard and said Howard what do you think of this idea that we start a foundation translational science we're going to do Investments not grants what do you think of all that because I think that's perfectly spot on I don't think he was prepared for the second question which was Howard would you leave your day job and come and work for us to lead this Foundation to be the first employee ever um and his day job at the time he'd been in Academia he had been in Industry he gave that up but he keeps a small private concierge practice because as I know I've worked with Howard now for going on six years he has only one true north what can all this do for patients and their families all right so it is at this point I'm going to turn it over ladies and gentlemen to the co-founder and the chief science officer someone who any of us at the ADF consider a good friend in a deep and respected colleague Dr Howard Phillip Howard thanks Mark for a great introduction um I'm not going to dwell on an introduction because Mark has really laid out a great landscape here I will say one thing perhaps coming at this as a geriatrician and a student of aging and an internist rather than a neurologist um I've I've thought a lot about the fact that we've had research on age teaching for well over 120 years and Alzheimer's disease is a disease of aging and old age and most of the therapeutic approaches to date that you've heard about or that we might discuss a little bit here today are really directed at the the neuropathology of the disease which is the plaques and Tangles but not really until recently directed against the biology or the pathobiology of the disease and so we sort of took the tack from the very beginning that there's tremendous amount of knowledge about the biology of Aging but none of it had been translated into developing new Therapeutics for all day for Alzheimer's disease and a good example of that is inflammation which is one of the Hallmarks of Aging but for many years there was no real concerted effort at trying to develop Therapeutics to reduce the inflammation that even Alzheimer's described in 1906 when he described the first person that had the disease so we've had a unique point of view over many years I can't say that probably five or six or seven years ago if you looked at most of the drugs and development they were against amyloid which is this protein that is present in the Plex and very little on these other alternative Pathways but today there's over 120 drugs in development and from our report that we put together recently over 75 percent of the drugs that are in development are non-amyloid non-tangle type of drugs which gives me great hope because we are on the verge perhaps of seeing the first drug approvals since 2003 so we've had about a 98 percent failure rate in Alzheimer's disease since about 2003 but for the first time we're seeing a lot of drugs being developed that are novel they're directed against Innovative mechanisms we're going to talk about that today and so that gives us great hope because even if these anti-amyloid drugs come to Market they're only having a modest effect on reducing the rate of decline of the disease about 30 percent let's say of a change in the rate of decline which is on the cusp I would say of being clinically meaningful but certainly statistically meaning full and and ultimately probably will pass FDA and we can talk a little bit about that but what we want to do is not slow the rate of decline of the Disease by 30 percent we want to slow it by a hundred percent we want to stop it in its tracks and I think the way that most of us now have come around to thinking about that is an is a good analogy is cancer and if you think about the early days of cancer treatment doctors were throwing toxins at cancer patients one at a time and then Sydney Farber and others came up with the idea that maybe we needed combination therapies and so they started doing combination trials and found out that combinations of drugs worked better than single therapies and then understanding the biology of the cancer cell it was recognized that there are many Pathways and by the way cancer is a disease of Aging in old age they recognized that there were many Pathways in the cancer cell that were disrupted contributing to tumor formation and so we developed biomarkers for cancer and then combination there therapies based on the biomarker something we call today Precision medicine so if you go in and you're coughing you get a lung tumor on your X-ray but with the biopsy is done and then the lung tumor itself the cells are characterized and then your treatment is tailored to the type of biology that your cells Express and it's been very successful right because now cancer is a manageable disease in many cases and that's the vision that we have for Alzheimer's disease we're going to have the first disease modifying Therapies in the history of the world probably come to Market in the next next few quarters and it's going to be very exciting but it's only the beginning of what I think we consider in the field the new era of therapeutic development for Alzheimer's which has been enabled by biomarkers the same way in cancer we're typing these cells we're looking for biomarkers that characterize patients now what we're here today we're very privileged to have Dr David Holtzman who is a professor of Neurology 10 Washington University we've been colleagues in the field for a long time and he's was chairman of Neurology at Washington University Medical School for about 18 years but I think perhaps one of the most proud things that I would like to say about David is that with an atdf investment a modest investment very early days David and his group spun out a biotech company called c2n which was very Innovative and risky at the time and I guess it was probably 10 or 15 years ago that we'd made that early investment but just but I guess in the last year or two maybe two years ago the technology resulted in the first blood test for Alzheimer's disease and this is really incredible if you had said to me five years ago I mean I've been taking care of people with Alzheimer's for 40 years we've been doing research on Alzheimer's for 40 years I've been doing research if you said to me there was going to be a blood test for Alzheimer's disease five years ago I probably would not really have believed it and certainly 10 years ago and I just want to say before I turn it over to David and ask him a question is that what enabled this modern era of having blood tests in addition to brain scans amazing brain scans for early diagnosis that we can use but having a blood test imagine how that's going to change care for people with Alzheimer's disease most people that get a diagnosis of Alzheimer's get it in primary care but primary care doctors are not good at making a diagnosis of Alzheimer's they're not doing a lot of cognitive testing and they're usually referring to neurologists imagine if there was a blood test that in the normal process of in the workspace of care of a primary care doctor just like cholesterol just like hypertension you do a blood pressure cuff you can measure hypertension for all major diseases diabetes you can do a blood test imagine somebody comes into the office and they have memory problems and maybe the doctor talks to them for a while the average Primary Care visit is about 11 minutes in our country I spend an hour with patients I'm sure David does too do a little bit of cognitive testing but you order a blood test and with about 90 certainty you can tell that person within a short period of time if they have Alzheimer's disease and then the workflow from there is what do you do about it and I'm sure we're going to talk about that it is not a nihilistic event in the course of tree of course of diagnosis and treatment and I'll just stop by saying that I believe that every patient with a memory problem deserves certainty around their diagnosis it helps with prognosis and I believe that that we all need to start with a certain diagnosis that we're clear about there was a study that the government sponsored Medicare that showed that doctors were wrong in primary care practice and even in dementia care practice about 50 percent of the time in making the diagnosis of Alzheimer's and that has conscious for care so the blood test is a revolution and so let me turn it over to David who is one of the inventors he's a founder of c2n which brought the first blood test to Market it's on the market now in 49 states and maybe you could tell us a little bit about the blood test dammit thanks can you hear me okay so yeah there's been an interesting and long journey 20 years ago we actually had some findings in an animal model that was related to Alzheimer's disease where we were finding that you might be able to see changes in the blood that reflected what was going on in the brain and then subsequently a colleague came to my lab and wanted to further investigate this and one thing led to another and we ended up developing what then was a what's still a pretty fancy way to essentially measure a very very low abundance protein using a fancy scale called a mass spectrometer and in doing that what we're able to do is to see when when certain proteins build up in the brain that are that Howard was talking about that are called plaques and Tangles these proteins get stuck in the brain and they don't come out as well and so what we're able to do is detect in the blood that they're not coming out of the brain and they're lower than they should be and that indicates whether or not this amyloid protein is building up and I think it's going to be very useful because as this as new treatments are coming out as Howard was mentioning there's a treatment you may have seen in the newspapers called the canimab that the Top Line results were announced about six weeks ago that while it didn't have a dramatic effect it seemed to the slow cognitive decline by about 30 percent over a year and a half and it will probably be the first approved treatment for Alzheimer's disease that affects the course of disease but you can imagine when treatments like that and other ones are being developed you're probably not every person if there's millions of people eligible for this are going to want are going to get a pet scan which is only available in some places or or spinal fluid testing which is doable but for millions of people it's going to be a lot easier if we can screen people with a blood test and get them the appropriate therapies that they ultimately need and and imagine trying to develop a drug for heart disease if you didn't have a blood test or cholesterol imagine trying to develop a a drug for hypertension right which affects 65 percent of people over 65. if you didn't have a blood pressure cuff you know that's where we've been with Alzheimer's disease but it's different now because they have a blood test now it's not only going to affect clinical care but the average phase 3 trial in Alzheimer's disease costs somewhere around 300 to 400 million dollars and we helped to bring the first diagnostic test to Market which was a brain scan uh pet scan that can see the amyloid in the brain that's amazing imagine you know you could do I can send a patient down the road to the radiology office get a brain scan and by the 24 hours I can tell them if they have Alzheimer's disease or not but it cost eight thousand dollars now if you're trying to do an anti-amyloid a clinical trial like David was talking about the drug that's coming to Market by biogenesei if 200 million half of the cost of finding the patients for the clinical trials is in the enrollment and recruitment phase and the companies have been using the brain scans to find the people that have amyloid in their brain so they can treat them with an anti-amyloid therapy now the blood test is about twelve hundred dollars if I'm not mistaken yeah I'm sure it'll be less than that when insurance pays for it but yeah it'll be a lot less so when we're screening people in the community to find these patients it's going to be a lot cheaper a lot less invasive and a lot less expensive and actually in one of the prevention trials that's now occurring with that same antibody the company ASI is using the blood tests to screen now instead of using amyloid they use amyloid Imaging but only after they're positive or negative on the blood test so and like many other fields of research this test has been enabled by modern technology because the old tests or some of the tests that are out there being developed by companies like Roche and Fuji Ray bio which has brought a test Mark they're not as sensitive as this Mass spectrometry test which is much more sensitive and able to do that so but all of the tests were enabled by new technology that had the sensitivity to pick up the minute amounts of these molecules in the blood and I think we're going to have more blood tests developed as we move down the line blood tests for inflammation part of the the blood tests that you've developed through your company c2n is called precivity ad correct right and it's actually a combination of amyloid which is the predominant protein characteristic of Alzheimer's disease and another molecule called apoe so just moving to Therapeutics for a minute and novel approaches to Therapeutics that are not amyloid apoe 20 of people there's three kinds of apoe apoe2 apoe3 apoe4 70 of people have an apoe3 or 8.3 out and and about 20 percent of people have an apoe4 but the but 60 of people with Alzheimer's disease have an apoe4 so we've known about this risk factor for almost 25 or 30 years but we haven't been able to drug it we know it's a like kind of a low hanging fruit so our foundation David has been trying to figure out how we can fix this apoe4 Gene make it into an aprily three or even make it into an apoe2 which is protective and it's really interesting this apoe molecule and its role in Alzheimer's and I thought maybe David has a unique program and that's something you could tell us about that sure so one of the apoe is interesting in addition to being the strongest genetic risk factor for Alzheimer's disease it seems to have played different roles in the course of the disease so one of the things it does not surprisingly like most of the risk factors for the disease it does affect when somebody develops amyloid deposition in the brain and that process occurs 20 years or so before people become symptomatic and I've worked on that a lot of people have worked on that but one of the things that's emerged recently is that apoe also affects the brain's inflat the response basically it affects inflammation in the brain so when you start developing these pathologies like amyloid and other changes there's immune cells in the brain called microglial cells that become very they're trying to they're essentially trying to fight off an infection they they see these proteins building up in the brain and they're trying to fight that off and in doing so they they secrete different molecules that are damaging to the brain so what we found recently in the last seven or eight years is that if you turn down how much of this apoe is made in the brain it suppresses the inflammatory response and that results in less brain injury so I think one of the approaches that we've been testing translationally in animals that I think will move into humans in the relatively near future is a way to decrease this apoe4 Gene and protein in the brain one way to do it is to give what's called it's a long name antisense oligonucleotides basically it decreases the level of this protein there's other ways one could do it as well but I think it's really worth trying to do this because I think what we don't have now in Alzheimer's treatment is a way to as Howard said do anything more than slow the disease a little bit and I think if we attack these other Pathways especially inflammation it's very likely we can really add on to what we have now yeah so so two things there was um one of the investigators were funding at the University of Southampton in the UK Cleveland Clive homes he showed and I think there's other other evidence that people can have this amyloid Protein that's characteristic of Alzheimer's in the brain but if there's no inflammation around that then those people don't progress very rapidly or at all and Alzheimer actually described these inflammatory cells that David was talking about in 1906 when he described the first case so we've known about inflammation for a long time it's a Hallmark of Aging we know that it accelerates the development of clinical symptoms in the disease and we have no Therapeutics for that either and we've been working on that for a long time and I have to tell you we met a lot of resistance in the field because the field was so focused on this anti-amyoid therapy but today one of the largest portfolios of Targets in the field is inflammation so it's a really exciting time because I think again we're trying to we're finally moving beyond these this sole focus on amyloid and if we can just get rid of and we're not being negative on the amyloid but it's just the first step in in this process and so there are a number of anti-inflammatory drugs being developed there's a company out there called Electro form which has translated some basic research on another Gene that was recently discovered called trem 2. and trim two is a receptor on these inflammatory cells that David just talked about the microglia in the brain and it's thought that by modulating The receptors these inflammatory cells do two things and one very positive way they're scavengers they're garbage disposal you know Waste Management cells they're out there to get rid of the amyloid plaques and so that's the natural defense against it but they're also inflammatory cells and when they get over reacted in the inflammatory pathway they get damaged so the challenge for the field is how to manage these cells in treatment to lean them to keep being garbage disposal managers and lean them away from being inflammatory cells that cause damage and so trim two was identified as one of the second genes in of many actually that are being discovered now as risk factors for Alzheimer's disease and there's a that's being translated and there's a company called elector that is actually in phase two now that is developing Therapeutics for trim two I don't know if you want to comment on that well yeah also just a personal story about trem 2. so in 2013 there were two papers that were published showing that this Gene called trem 2 is a strong risk factor for Alzheimer's disease it's not as common as the apoe4 allele of a buoy I think only one or one percent or so people have this particular risk mutation but when this was announced I looked at this and I go oh my gosh so I walked literally downstairs from the eighth floor where I am to the seventh floor to a guy's lab named Marco Colona who had cloned the trem 2 Gene in 2001 he had been working on it for a long time and we immediately started to collaborate and what what Howard said Is Right it looks like if you turn it on it this inflammatory effect is kind of good during the early phase of Alzheimer's disease when you're pre-symptomatic but once you start getting a lot of damage in the brain you might want to kind of turn it down so that's exactly the challenge in the field now is how do you when do you tweak it and how much do you do you tweak it up do you tweak it down so we're trying to do a lot of studies in animals to figure that out before we go Hog Wild although elector is trying something early we'll see what happens and just as an anecdote I had a patient several years ago a beautiful young woman she was about 45 and she had a horrible Progressive dementia with no real history in her family and we did some genetic testing on her and it turned out she was apoe4 she had two apoe4s so that alone would cause her to have the disease onset about 10 years before most people so instead of 75 65 and so much greater risk but she also had a mutation in the trim two Gene called r47h so she had two of the main known genetic risk factors for Alzheimer's and she had a really rapidly Progressive dementia that she she died at about age 52 from that and what we're trying to do now actually through the foundation and through this particular donor who this patient was his wife is establish a clinic at the University of Alabama of people with this rare r47h mutation so we can better understand why it's so pathological why it causes an acceleration of the disease and sort of from an orphan designation maybe develop drugs for r47h to fix the r47h gene but what's what these two stories say something about is you hear a lot about genetics in the newspaper a new Gene was discovered apoe4 was discovered like 30 years ago and it's 30 years later and we still don't have effective therapies and what I want to say is it's a long way from discovering a gene and developing a therapeutic for that Target it's a very long way and Drug development is really hard so actually this this having two copies of baby before anatrem 2 mutation it's interesting last week we published a paper exactly about that topic and what happens is when you have that unfortunate combination you're these microglial cells the inflammatory cells build up a lot of lipids inside of them and they can't get rid of it and that's probably somehow leading to this really strong inflammatory response so it's that's something that should be ultimately to be able to develop a treatment for that I think and I just wanted to add also that um this aprily for the apoe protein in general has many functions if you do a Wikipedia on it's a list of functions that it seems to have is enormous so people including us were trying to develop drugs based on one or two or three of those Pathways that apoe4 is involved in and then we sort of realized and I should say Rod Crystal who's was is the chairman of genetics at Wild Cornell and is a very successful bioentrepreneur he said this is a gene a genetic abnormalities let's develop gene therapy for it so what we did was we started funding him at Wild Cornell and helped him spin out a company and invested in the company called lexio and what they're doing is apoe 2 is protective apoe4 is the damaged one if you take people that have two apoe fours they're the ones that are at greater risk imagine if you could change their brain so that they actually their brain was able to make apoe too because we know that people who are apoe two four right they're protected and they have neutral risk so what we're doing and what what Dr crystal is doing and while Cornell is he's doing gene therapy for the apoe4 abnormality he's taken a virus it's approved by the FDA it's a non-infectious virus and he's putting the apoe2 gene into this virus the virus with the apoe2 gene becomes the drug inject the virus into the spinal fluid it goes throughout the brain and the Brain starts making apoe too and he's in phase one he's going to report the results at a public meeting next week he's tested about five six patients at this point it seems to be a safe therapy and he can show that with the gene therapy people who are double E4 make apoe2 protein whether that's going to work to slow the disease down or offset the risk for on the apoe4 risk we don't know yet but it's another approach another novel approach to the whole approach to novel Therapeutics also David there's a strong vascular component to Alzheimer's disease I thought maybe you want to talk about that because I know you've been interested in that for a long well there's two things I think as people develop cognitive impairment say over the age of 70. Alzheimer's disease contributes to many people that do develop cognitive impairment but this probably the second most common cause of of damage in the brain and in this in sometimes overlapping people is is developing um small Strokes basically or vascular damage so one thing that's already been shown to it looks like it's very effective at delaying the onset of dementia is outstanding blood pressure control because it decreases your vascular risk but in addition to that one of the other things that happens in many patients with Alzheimer's disease is they develop this amyloid protein we're talking about not only in the brain but also in the blood vessels and when that happens that can also decrease blood flow to the brain and so just thinking about Therapeutics we don't have good therapies for this this problem where amyloid builds up in blood vessels called cerebral amyloid angiopathy so one of the other things we've also worked on recently is a way to get rid of this cerebral amyloid angiopathy by targeting apoe which also contributes to that particular problem so I think there's a variety of things that could be worked on some of which are obvious just prevention blood pressure control diet but also maybe some targeted therapies for depending on what the vascular problem is well I want to get back to the blood pressure control thing but also and and the spirit of what you're hearing here is novel approaches to treatment Beyond amyloid that you read about in the newspaper so we've funded a study Professor Strickland at the Rockefeller University several years ago and he showed that this very potent very important coagulant protein called fibrinogen which throughout the body if you get a cot or whatever it's very involved in helping you to form a clot and what he showed was that fibrin which is a derivative of fibrinogen that's activated by damage to the blood vessels but it's really tightly to the amyloid protein and these fibrin amyloid complexes deposit in the blood vessels even the small valves of blood vessels and he showed this in an animal model and when they're deposited in the blood vessels they cause inflammation around the blood vessel and it's thought that it's possible that one of the ways that you can create a link between systemic vascular disease and the amyloid plaques is The Binding of this fibrin to the amyloid the deposition of these complexes which are very stable and the induction of inflammation inside the brain as a result of that a company was spun out of UCSF called thorini and they're pursuing this strategy of trying to interfere with the fiber and amyloid interaction in blood vessels with a small molecule and we're very invested in this company and we're very excited about this possible alternative novel Innovative approach for a number of reasons not just to reduce the amount of angiopathy in the brain but also because platelets and these coagulation factors are very involved in the risk of diabetes and hypertension and even perhaps atherosclerosis as risk factors for Alzheimer's it kind of creates that link between these systemic diseases and the amyloid plaque formation and the characteristic pathological Hallmarks of Alzheimer's disease which kind of leads me to another novel pathway that's being pursued these days which you might have heard about and that's the fact that diabetes is a risk factor for Alzheimer's disease and so many of you might have heard about metformin and everybody that I meet wants to be on Metformin and I would say about 10 or 15 years ago we sponsored a clinical trial of Metformin for Alzheimer's disease up at Columbia University a professor there named Jose luxinger and as a result part of our return on philanthropy is not just investing on by in biotechs and we've made I think upwards of about 130 investments in small biotechs over the last 25 years but in our investments in in Academia where we've made hundreds of investments in new Therapeutics we're really interested in in the metabolic changes the insulin resistance that occurs with aging diabetes and in particular the fact that there's insulin resistance in the brain and Louis I'd like to introduce the topic is to say what's the first thing that happens when a diabetic gets a low blood sugar because they've taken too much insulin and it blood glucose below goes below 60. what's the first thing that happens they go unconscious the brain is three percent of the body weight and at any given moment it's consuming 20 to 25 percent of the energy that we consume or use through basically glucose and oxygen so that's kind of an example of how insulin resistance with aging on a chronic basis can lead to neurodegeneration because these cells are very dependent they're the most metabolically active cells in the body the neurons but but they're also at Great risk for insulin resistance and so there's a lot of repurposing going on of diabetes drugs to improve insulin resistance with aging and this particular doctor just got about a 40 million dollar Grant from the government to do a clinical a large clinical trial of Metformin for Alzheimer's disease and there's a company called Novo nordis which is based on some work that we funded at the Imperial College of London using a different kind of diabetes drug called The glp-1 Agonist and I like to sing this song for you because a lot of you will recognize it you watch The Daily News whatever's permission if you've ever heard of this drug ozympic it's on the Nightly News it's oh oh oh okay well no one we we funded some work of a drug related to no uh ozampic called Lira glutine at the Imperial College of London and Paul Edison there showed that lyric glow tide would be basically probably good small trial for Alzheimer's and now Nova Nordic is conducting a 3 000 patient uh clinical trial of the oral formulation of the ozempic for Alzheimer's disease to reduce this Metabolic Effect David I don't know if you want to comment on diabetes as a risk factor or some of the new therapeutic approaches to that well I think there's two things with diabetes one it's obviously also it increases your risk for cardiovascular disease which affects the brain but there's also these other effects where it seems to affect brain metabolism and that's where some of these newer some of the treatments you're talking about might play a really important role in improving brain metabolism by by using some of the diabetic new treatments and you know there was Alzheimer's described a novel disease that you named after his friend back in 1906 called binswanger's disease which I'm sure very few people except maybe Bonnie Davis has heard of and binswanger's disease is a dementia a vascular form of dementia people with diabetes and hypertension and we know now that those are the two leading medical risk factors for Alzheimer's use I think alluded earlier to like the Sprint mind study and prevention and the role of hypertension and as a risk factor for Alzheimer's could you elaborate on that yeah I think well this this Sprint mind study that was done looked at people who were late middle age and tried to do relatively tighter blood pressure control and they clearly showed that the risk of of developing very subtle cognitive decline was lower in people over several years if they did the tight control versus not and what was described years ago this binswanger's these that's where there was all you know a lot of the a lot of the area under the cortex called the white matter was really being destroyed by small blood vessel disease from hypertension diabetes but what we can see now is that virtually everybody over the age of 60 has some damage to the small vessels but the question when it gets a little bit more than just a small amount that's where you we really need to be doing prevention of that that initiation phase of small vessel disease and that's where blood pressure control diabetes and maybe other things could probably play a big role in in the contribution of that to what we also see with Alzheimer's disease so we have two minutes left okay that went fast well then let me just say that we're repurposing hypertension drugs for the treatment of Alzheimer's disease as well the Angiotensin receptor blockers but we don't have time to talk about that yeah that's what I was going to say so when we talk about prevention um we're talking about many risk factors and the studies that show it but probably 40 percent of the cases of Alzheimer's could be prevented and there's clinical trials going on of prevention going on but one of the interesting thing that David's been doing is investigating sleep as a risk factor so maybe you could tell us about that really I think what one of the things I'll say is that we we I was not studying sleep at all until around 2007 when a graduate student in my lab was doing exploratory studies and happened to discover that the different proteins that make up the Alzheimer's disease pathology like amyloid and Tau they actually fluctuate in the brain with the sleep wake cycle they go up the longer you're awake and they go down when you're sleeping and that actually turned into a science paper we published and and the implications of this were that when we took animals that developed this pathology and we sleep deprived them they develop a lot more pathology over a relatively short period of time we also showed that if you improve their sleep at this time we used an agent called a erection receptor antagonist now these are on the market to help sleep that actually suppress the pathology so I think this I think this is leading to an Era where you might be able to test whether promotion of sleep in ways that don't cause a problem might be ways to delay on you know be a prevention for Alzheimer's disease I think that's what we'd like to test now in humans yeah we're hoping you'll send us an application so we can fund that trial and but you mentioned these are antagonists says and do approach to sleep and you sort of feel that the drugs like Ambien and that class of drugs is not good for you right right because um the classic sleep promoting drugs like Ambien other Gaba a agonists basically they they do cause you to sleep so they're good for that but they you can't if you take them for a long time you can really get side effects from them you can get somewhat addicted to them whereas this this new class of Agents the first one that came out was belsomra but then now there are several other ones basically they turn on the Sleep Center of your brain and not affect all the other cells in the brain so they just cause you to immediately go to sleep and they don't have some of the side effects that you see with other agents so it really might be something worth pursuing are we on time of course if we just go to q a mark you get one last question before everybody gets the questions go ahead well I mean there's so many interesting things going on with uh prevention now and we think we can prevent maybe 40 percent of the cases some of the new risk factors are like hearing loss social isolation and so on and you were you were talking about the gut microbiome and I found that I think that's really an emerging issue now we're all hearing about the role of the gut and the microbiome and the gut in disease and there's some evidence that might be involved in Alzheimer's disease right there's a there's a few so there's a lot of studies in human health that have shown that in certain disease conditions the bacteria that are in your gut which have more more bacterial cells than we have human cells in our body in all of us if you manipulate them um one they're a little bit different in different diseases the composition versus somebody who's normal but that if you manipulate them in different ways that you can sometimes have health benefits and our lab has been finding and we have a paper that will come out very soon on this that if you um alter the gut microbiome in animal models that develop Alzheimer's pathology that you can strongly suppress the pathology now how to do that in humans in a way that will I think it needs to be tested because it's a lot more straightforward the reason this is probably happening is that the gut microbiome regulates inflammation outside the brain but then that affects inflammation in the brain and so that's why this is an exciting new Target to think about yeah I'll just close by saying Mark that one thing that David's mentioning is systemic inflammation and that's a Hallmark of Aging arthritis causes inflammation all the diseases that we suffer diabetes atherosclerosis these are all diseases of inflammation and the example I like to give to link the predominance of systemic inflammation with aging and Alzheimer's disease in in the brain is if you think about it when we teach medical students how to diagnose pneumonia we look at cough and fever as signs of pneumonia but when we look at older people that have pneumonia the first symptom of systemic inflammation from pneumonia is confusion and delirium polar people don't develop a very effective fever response or a cough but so if you're taking care of an 85 year old that's developing delirium one of the first things you want to think about is either pneumonia or an urinary infection and it's just a really you know very striking example of how systemic inflammation can trigger the brain and affect brain function good so we're going to open this up to q a but how about a round of applause how fabulous [Applause] David you're laying down a really good marker for our first in the series this season to how we're going to beat this as we go forward so um just raise your hand I'm going to bring the microphone around and you can ask questions first of all thank you very very much I think the whole audience is so appreciative of what you you do um so I wanted to to continue off of what you were saying about the gut brain sort of connection and therapeutically you're saying Therapeutics could be developed to help Alzheimer's but if you look at it in the other way because many many I think millions of Americans have Crohn's IBS and other related uh problems with with with their gut is that a risk factor for Alzheimer's I don't think we know the answer whether um Crohn's is a risk factor for Alzheimer's disease but one of the things I've found intriguing in the last several years is that when people develop diseases like that now they actually get treated with agents that suppress the immune response things like Humira other anti-tnf antibodies things like that I think that is probably if anything would be protective against Alzheimer's disease but the question of whether the disease itself would put you at risk I don't think there's good studies that have shown one way or the other that would be the case but there was a study of anti-tnf antibodies of Humira for Alzheimer's disease and it was a small study which suggested that if you block a tnf alpha which is a major inflammatory hormone call it from all of these diseases that you could block the effects of systemic inflammation on the brain and actually about 20 years ago I showed that there's elevated tnf Alpha in the blood of people with Alzheimer's disease and that's again with c2n and new biomarkers I think one of the challenges that we have today even through our Diagnostics accelerator which we we have a hundred million dollar program with Bill Gates and Jeff Bezos and David Dolby and others like that to develop new biomarkers and one of the main focuses of that program is looking at these novel inflammatory markers in the blood that promote as I said before brain inflammation that's bad for your brain so regardless whether it's Crohn's disease or whatever any inflammatory disease or activity in the in the body affects the brain foreign you mentioned briefly tell how does Tau fit into this and how does Tau research fit in that's a that's a great question so um in Alzheimer's disease when you follow people with all these different tests we can do now for research purposes what what looks like happens is that in somebody that ultimately develops dementia from Alzheimer's disease literally 20 years before that this protein amyloid starts to accumulate and accumulates over 20 years till it gets to its almost as much is ever going to be in the brain but right before people become symptomatic with memory loss or other cognitive decline this Tau protein starts to build up and the buildup of the Tau protein is what strongly is linked with the damage in the brain there's a lot of people doing research on Tau now including what is the structure of the protein that changes so that it builds up what response is it eliciting in the brain that leads to damage that's one of the main things I'm working on now is how is it leading to damage and a lot of the evidence looks like it's stimulating these microglial cells these inflammatory cells to damage the brain but there's a lot of people now more people now are working on it than previously that's for sure and I might say if I may about c2n what I'm excited about is several companies are trying to develop cow protein Diagnostics which are looking like they might even be better than what's currently on the market through c2n which is the amyloid blood test c2n and other companies are going to have tablet tests which will be even better yeah those are those are already being shown c2n's new tests as well as other ones I mean if you combine the tile marker with the amyloid marker it's as good as getting spinal fluid analysis for whether you have Alzheimer's changes it's really really accurate it so so if I could ask a question if somebody in the audience are in your practice or whatever wanted to get the c2n test which is the only test really on the market today um what would they do um right now they have to see a physician that then orders the test you can't just go and get the test without a physician ordering it and and I think in 49 states there are places that you can go to a physician to order the test so yeah and there's a website it can tell you the information about where in your area you could potentially obtain the town do all doctors offices have access to the test or how is the role outcome they it's it's been somewhat slow for clinical purposes because I think the main reason is that for any anything that's done in human beings clinically for most people they needed to be paid for by their insurance and a new test like this won't typically it takes a while to get it approved because you need to go to the FDA you need to go to center for Medicare and Medicaid and it's a very long process to submit all the information to them to but it is available you can get it done and um and so yeah no it's you just you can if anybody is interested I can send them information where they can how they can do that and I know a common question that I get and you get all the time is why bother getting the test if you're not symptomatic let's say if you're symptomatic it's a different equation right because you want to have some certainty around the diagnosis which that's important really important but what about if you you know your father and mother had Alzheimer's and you're 40 50 years old what would you would you counsel your patients to do right well so two things one right now this blood test or any other test isn't only available clinically if you have symptoms we're not a lot the company's not even allowed to do it on people who don't have symptoms having said that I think the biggest use of a test like this is actually going to be in mid life when the disease really starts again 20 years before the symptoms because these tests can pick that up right when it starts and I think in the next few years it should be become it should be a huge impact on people let's say you get to a certain age let's say you hit 40 or 50 you get a test like this if it's negative that's great wait 10 more years get again if it's positive then you might either start a therapy that might be approved by then or you get in a trial or you so that that's where I think it's going to have an even bigger impact so if one is able to um take a test why wait until their symptoms why not take them take the test but when there's a certain age and do something about it if there is yeah well I think why not take the test earlier when you're normal I completely agree with you but the Regulatory Agencies won't allow companies yet to do that it's not has nothing to do with it's just the law I mean they they won't let there's a concept called the value of knowing it's a health economic concept and health economists use this to try to quantitate the value of knowing for an individual or a population so what's the value of going to anyone in my practice that I'm counseling where there's let's say a family history and say they're 50 and they say Doc you know I heard there's a test out there should I take it right and so one person may say I really want to know I want if so I can do everything I can I'm going to exercise every day I'm going to eat a Mediterranean diet I'm going to sleep like crazy you know and the next person probably more like me I don't want to know this is too scary you know I'm going to wait 20 years to find out so I think the the rollout of these tests in clinical practice for prevention is going to be within the context of what we call in medicine shared decision making where the doctor is there to inform the patient about the value of a test and the patient is there to express their wishes and I think it's so it's not going to be black and white it's not going to be like cholesterol where the government says everybody should be screened we're not there yet but there's a value in it but it might be there it might be there in the future I think that just you need to people need to show evidence that it's useful to get the test and I think once that's done it will be and there are prevention trials going on maybe you want to talk about the adhere trial or some of the other trials right right well there's there's two trials that are prevention one will read out after a six to seven year trial period which is um called the A4 study which is using one of the anti-abate amyloid antibodies from years ago called solanizumab that will read out in the next uh I think six months actually actually I don't know if you know that came out of my lab but in any case um the the what's a really exciting prevention trial though is this lacanumab antibody which was will likely be approved in the next few months and that's the that's the Biogen that's the ACI Biogen antibody so that antibody um is now being tested in people that are cognitively normal and they get up they get this c2n's blood test if it's pot and they have to be between I think it's 60 and 80 years old cognitively normal you get the blood test if it's positive then you can get in the trial and then you get a series of other tests and then you get randomized to either receive that treatment this antibody or not it's a five-year trial and the goal is to see not just whether the antibody removes amyloid but the weather delays the onset of any cognitive decline and you know five years if you watch the Nightly News and it's always like these are happy people with cancer that are taking some drug and it's it's at the very bottom in tiny print you can hardly read it because it's white on white and it says this drug improved life expectancy by seven months and then the next screen says and this drug caused death vomiting diarrhea so the whole time you were on the drug you were sick okay so here we're talking about possibly delaying the onset of Alzheimer's Disease by five years and there's been studies that show that if you know really simplistic reasoning here that if the average age of onset of symptoms from Alzheimer's is 75 and if the average age of death is 80 and we could delay the onset of Alzheimer's Disease by just five years through what we currently know about exercise and so on and a drug add-on so it's like the heart disease prevention you'd lead a healthy lifestyle you manage your diabetes and hypertension and you take a Statin in this case maybe it's you do all those things and you take an anti-amyloid antibody bottom line is if we could delay it's a realistic goal if we could delay the onset of Alzheimer's by five years we would reduce the number of people suffering by out from Alzheimer's by 50 percent and that seems like an achievable goal to those of us in the field I think just a question about funding how much funding does Alzheimer's researchers get from the NIH of the total budget I know a large percentage goes obviously cancer therapy Etc but yeah so when my mentor who was sort of the person who he won the Pulitzer Prize in 1976 for writing a book called Aging in America why survive which brought the to the attention of the American public and the world really what he predicted would be the coming epidemic of Alzheimer's disease and he went with a woman named Mary Lasker who was a founder of the National Institute of Health in 1948 through con through a congressional act and the two of them went to Congress and said we need a National Institute of aging and we need that that Institute to focus on Alzheimer's when David and I went to med school in there when I went in the early 70s Alzheimer's were not in my textbook when I was diagnosing people as an intern and a resident I never made the diagnosis I never heard of it until I saw my first patient in an in a nursing home where I happened to be in 1980 and so when when Bob Butler started he got the Congressional Act they started the National Institute in aging they had a very tiny budget and he did a survey of how much research was going going on in 1976 in our country at a time when billions of dollars was being spent on the war on cancer and heart disease and we spent as a nation 625 thousand dollars on research and Alzheimer's most of them were caregiver grants now had to build the field okay when we when I started in this field in 1980 nothing was known the Amway protein wasn't discovered until 1984. build build so about five or six or seven years ago the National Institute on aging and the Alzheimer's budget was pretty small it was like in the order of a few hundred million dollars and just to give you an idea today the National Institute on Aging is the third largest Institute at the NIH has a budget of about 3.6 million billion dollars and so we've come a long way as my story yeah it's just a little bit less now than cancer not much so it's really gone up a lot thank you well how much time do we have a few more questions well you know I thought if there's no questions I thought I'd follow up on something practical actually and we talked a little bit about hypertension as a risk factor and you talked about white matter hyperintensities and you know when we get the result of an MRIs because we always pretty much do MRIs of the brain on people who are trying to diagnose the the very frequently the MRI comes back that there's these white matter hyperintensities in the brain and the Radiologists that I work with they're still saying this is normal aging or whatever and we know now that this is not all normal aging but it's a reflection of what we call microvascular disease of the brain the blood vessels you're much better than I am at this but the blood vessels of the that have Supply the brain are the carotid arteries these huge tubes that come in and then they dive deep and become smaller and smaller and they're the end vessels of the blood and so that's where the vascular pathology is and maybe it presents slightly differently subcortical symptoms and so on but you know there there are ways to diagnose this vascular component and even to use it as a biomarker and I think the National Institute of neurological diseases is doing a good job in trying to promote the effort and research on these on the microvascular changes that occur with aging change the practice of you out there that these microvascular changes that we see all the time on MRI are are benign and nothing when they're really not and we see when we see them along with vascular pathology people probably progress more rapidly oh I know I think you're right I mean sometimes you see patients where you know that the predominant cognitive change they have is is due to this vascular damage and they present with a different syndrome and so it's a little but often it's a it's a real mix and I think the MRI in conjunction of course with the history and everything it can be very helpful in determining how much uh that contribution might be to their problem what the national the national logical Institute is working on a lot is trying to better understand how vascular dysfunction Beyond simply these white matter changes might be linked to disease and whether you can actually Target the vasculature in some way therapeutically right and um there are drugs you mentioned about treating hypertension one of the things that we're trying to sort out and I think the field is coming to is which antihypertensives are best for preventing dementia and which class and one of the things that I think is emerging is that the Angiotensin receptor blockers like Candace Arden and telomosartin are neuroprotective and we sponsored a clinical trial in Emory that's going to be reported at the next meeting and next week on the value of candesartin in the treatment of people with Alzheimer's disease right well that's great I think that that we those kinds of studies are just now finally coming to fruition so it's important because so many people are taking these kinds of drugs and it's be good to optimize which ones would be best for this purpose so and maybe the last thing I've over the years there's there are companies out there like neuroquant nicometrics and we have started a company called ADM DX about 15 years ago and they're using artificial intelligence and computerized models to read the MRIs of the brain that you and I are ordering on practically every patient and it's so in the old days and even today I get a report back from the radiologist and it says there's some atrophy in the brain and it's probably related to normal aging but we don't really know and can't really compare but then I always order the neuroquant which is available in my radiologist's office and they give me quantitative information and it says this patient's hippocampus is at one percent of the volume of what should be normal and this is probably Alzheimer's just based on the MRI right now we do the same thing at our Medical Center where the it because a lot of these methods were also done at Washington University and barn shoes hospital they actually whenever we get an MRI at our Medical Center and they know who's getting the MRI then they will do all of this all the very very detailed measurements of all the brain regions quantitatively just like what you're talking about it can be very helpful actually and I think that um there's this NTN criteria that we're using amyloid Tau neurodegeneration measured by neurofilament which I imagine c2n and other companies are going to commercialize along with gfap using big words here and then a v component of the vascular which we're funding the Mayo Clinic to develop that maybe you want to talk about that Paradigm well right so these biomarkers that we've been discussing you can now in in the blood measure the amyloid component the tile component there's another component that indicates how much damage is occurring in the brain this neurofilament protein that definitely will be added into these panels for sure I think many of the other neurodegenerative diseases that are not Alzheimer's disease so some of the other relatively more frequent diseases are things like what's called Lewy Body Dementia or Parkinson's related Dementia or phrenotemporal dementias picks disease and other Related Disorders we don't have good biomarkers for those diseases and I think those needed to be developed so that you would get initially when you come in for a diagnosis you get a whole panel of things to really nail down well I have this disease alone are these two diseases or and and not only do you have them how far along are you in the Disease by how much damage there is ongoing yeah I'm kind of excited of the day when neurofilament becomes part of it because it's kind of talking about disease activity I think we see that in other neurodegenerative so we can tell people how active their disease is and it's being used in clinical trials and and maybe gfap would be a marker of astrocytic inflammation yeah there's a really dramatic thing happened a few years ago there's a childhood disease called spinal muscular trophy where babies are born and within a few days they become almost paralyzed and they they die within a year and their treatment was developed for this disease called nusendora and there's now two but that was the first one and basically it used it's a fancy gene therapy that these kids no longer die they they can now live what looks like pretty normally but one of the ways it was detected that that drug was working is they measured this neurofilament protein which was very elevated because of the damage in their central nervous system and then it just plummeted when they got the treatment we can actually see the same kind of thing in animal models where we block neurodegeneration this protein neurofilament in the blood goes way down so it correlates very well with how much damage is going on well I want to thank David for joining us oh hold on you want to close oh yeah we're going to have a couple of questions David take us out five years five to ten years blood tests Alzheimer's what do you envision what do you hope for I think the probably the most exciting will happen between by about five to ten years from now is that the current Test Plus additional ones will be available so that you can actually determine many years before that you're actually developing a problem but you're normal and then you can do something about it I think that's where I think things will be hopefully sooner rather than later how long it will take I'm not sure but we can already detect the disease in the brain with the blood test 20 years before symptoms start so we ought to be able to take advantage of that um and maybe whether some of these new treatments get approved not just for treating people with symptomatic disease if they get approved for treating patients pre-symptomatically then that's going to be a great place to be and Howard kind of same question for you with a different twist so that's where we're on the blood test five to ten years from now what are you most excited in the field as a whole take us out five years I think these biomarkers are just going to really expand and it's going to enable like we talked about Precision medicine typing patients according to their biology and then hopefully developing new Therapeutics that are the non-amyloid non Tau type of drugs and I I do think that one of the major advances that's happened over the last several years is not just the availability of biomarkers to enable the way we do clinical trials but a tremendous amount of knowledge about how to do clinical trials more precisely particularly measuring things like cognition and there's new technologies that we're supporting and are in development through the Diagnostics accelerator and other things where you know in the old days it took six hours of a neuropsychologist to do the neurosite tests in in the clinic or in in clinical trials and they took a lot of work it's very expensive and now we can do the same thing on the smartphone and so what's going to happen is both in the community there'll be passive capture of cognitive function on a smartphone with artificial intelligence and that'll be applied to screening people using things like speech and language so if you remember towards the later days of the Reagan Administration and even sometimes people complaining about President Biden his speech isn't the same way as it was anymore and there's Technologies now that can pick up very early Alzheimer's disease using speech and language parameters on a smartphone so we'll be able to pick people up with very early Alzheimer's in the community it's going to make clinical trials much more effective and I think you know getting back to what I was saying I think this new era of our efficiency and the preciseness which with we're able to do trials at a much less expensive number is going to lead alongside all the advances we're making and recognizing these other Pathways I'm sorry to give you a long answer Mark but but um you know looking at the fact that 75 percent of the drugs and development now are non-amyloid non-tau Pathways the short answer is I think in five years we're going to have several drugs to Market that that are going to address different Pathways and Howard just to finish it off what would that mean for you patience then versus patients today I think we're in a phase of hope you know we can offer people hope in the old days there was no hope you know doctors would say I'm sorry memory loss you have Alzheimer's go home and don't come back you know um you know I think we can offer people hope now that there's we're having breakthroughs and I think there'll be treatments and you've heard a lot about prevention today I mean the real goal is prevention and I think we can offer people tremendous hope about prevention that I I never would have imagined 5 or 10 or 15 years ago good Dr hedness and Dr Philip we have some reports and Heidi and Tom I think we're off for a really strong start for uh for this season hey one or two things just at the end here one there was a very good question I think from this side of the room about NIH funding and the point I just want to make there the overwhelming majority or bulk of that NIH funding it's going to good research but it's not the precise research you're listening to here research that's spinning out academics into biotechs and re signs that's directly into biotech funding these phase one and phase two clinical trials that are these Nom amyloid trials I bring that up for two reasons and I wouldn't be doing my job if I didn't one of them is that the way to most precisely get there at a hundred cents on the dollar goes right there is Investments and donations and philanthropy to the addf and then those also of you that are here that also um invest your dollars in a private sense that you do these companies they're moving towards something but they need to move faster they need Capital so there's both philanthropic contributions and there's private Capital that can go into these countries and that's not quite precisely where the NIH funding is so we're thrilled how much more is going in NIH but the tip of the spear is what you're what you're listening to here and that tip of the spear if you take away nothing else from today was this hope and realization and it's right in front of us that these combination therapies think about this could push out Alzheimer's and Dementia five years and we heard today average age 81 somebody passing no offense anybody over 81 here um but think about that the humanity saved you know your children your grandchildren your intellectual capacity stays with you until you pass and that's just amazing that's what these two doctors have been bringing to us tonight that's what the addf brings to you thank you very much everybody [Applause]

Channel: Alzheimer's Drug Discovery Foundation

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Id: 8GL82pKM73U

Length: 71min 52sec (4312 seconds)

Published: Mon Dec 19 2022