Tomorrow’s Breakthroughs Today: Dr. Frank Longo

before i introduce howard who will take the rest of the evening here i want to comment a minute about the addf and what you're going to hear tonight leonard lorde over a decade ago came up with a phrase when he was talking about the addf he called it hope is on the horizon and tonight you're going to hear that hope is actually here and i know that's something you don't hear a lot about hope with alzheimer's i'm just going to give you the 30-second elevator spiel about the addf founded 24 years ago by the lauter family they made a decision they were only going to fund science and a certain type of science it's called translational science how do you go from the bench to the bedside how can you speed interesting signs so that it's actually treatments and preventions and ultimately cures and the water family decided that they were so they're only going to fund what often is called valley of death science interesting ideas in the lab but they're not so de-risked that big pharma is coming in to take them through to patients right so somebody has to pick that mantle up the lauter family did that about 25 years ago the lauder has also decided they would not give out grants rather they would give out money to academics and to biotech companies in the form of investments and those will go as investment so if that academic institution or that biotech saw some kind of commercialization of what was being funded the adds the addf would get a part of that and then put it right back into the science a way to speed the science in a very innovative way and the other thing that i will let you know is that the science you're going to hear about tonight is called a big banner over it the biology of aging and what do i mean by that um i am delighted to see that i'm staring at two engaged men one in the first row larry leads larry put your hand up again the other in the second row which is josh lauder put your hand up again and you may notice there's a difference in their ages but i will assure you while we sit here both of them are aging we are all aging it's true and we age in different ways okay and dr phillip who you're going to hear about talks about seven different pathways that are involved with your aging could be genetics could be something like inflammation could be vascular it could be any number of things and what the addf for the last 10 plus years has been funding this concept that we all age but if we age and our memory starts going if we age and we start forgetting our children's names if we age and we can no longer communicate with the outside world that's not normal aging and so what dr phillip and the board of the addf came up with this biology of aging and we're going to fund all these shots on goal across these seven areas and we're going to see where it's going to take us the last thing i'm going to say before i turn it over to dr phillip is the following i know today in my lifetime right now if my cognition started to go i have options i have two children who are both married late 20s early 30s and i know in their lifetime they're going to have prescriptions around prevention prescriptions around combined therapies and something called precision medicine and i'm also thrilled to tell you that i have a nine and a half month old grandson his cutest baby ever and i know in his lifetime so long as he stays on prescriptions that doctors would give to him if his cognition started to go in his 60s 70s 80s he's not going to die from alzheimer's not a lie here this is exactly what the addf is funding today last piece thank you to the lauter it's because of the lauter family today yesterday tomorrow anybody who donates to the addf the lawyers take care of all of the expenses so every nickel of the donation goes directly to the science you're going to hear about tonight it's enough of me i want to give you our co-founder with the lauter family of the addf dr howard phillip who's given his life to the signs of aging the life his life to the improvement of cognition he's our co-founder and chief science officer dr howard phillip thank you mark thanks everybody um i thought i'd give a little bit of an overview of where we've come in just in my professional lifetime i saw my first patient with alzheimer's probably in 1979 which was about 40 something years ago up until that point i had been training in medical school seeing patients in an internship a residency fellowship taking care of hundreds and hundreds of older people and never made the diagnosis of alzheimer's in fact i never heard of it and when i went look back in my textbooks alzheimer's disease was not in my medical school textbooks and um the first time i saw a paper with alzheimer's disease was when i had the privilege of visiting what's called a teaching nursing home i was interested at that time in geriatric medicine and i walked into this very beautiful architecturally designed building that had 300 rooms 300 beds in it and they were all very nicely with furniture and all that um and they took me on a tour and i saw these people that had alzheimer's disease and they were bedridden and couldn't walk and couldn't talk and couldn't bathe themselves and for me i um actually wrote and published my first neuroscience paper in 1971 which is almost 50 years ago and so i pursued neuroscience research and putting those two things together a lot of older people geriatric medicine discovering this disease of alzheimer's and the love of neuroscience it just became unnatural for me to kind of spend my life at um so when i started uh nothing was known about alzheimer's disease i mean literally we we knew nothing about alzheimer's disease we knew what what alzheimer had described in 1906 but what happened was that alzheimer described dementia in a 52 year old woman who was clearly because she had dementia she was obviously had a disease but up until about 1968 1970 senility was thought to be a normal part of aging so in other words when people started losing their minds and becoming childlike everyone thought that this was normal and what changed was that some pathologists working in london in the late 60s decided to do a very simple experiment they looked at the brains at autopsy of older people who died with dementia with senility and they looked at the brains of older people who died without senility and what they found was the same pathology that alzheimer's described in the 52 year old woman the plaques and tangles in the old people who were senile and so it was on that day in human history that senility went from being thought of as a normal part of aging oh grandpa's senile to being understood for the first time as a disease of old age and when my mentor robert butler realized this he wrote a book called aging in america and got the pulitzer prize in 1976 for writing that book and then became the first director of the national institute on aging and when he went there he looked at how much money was going into alzheimer's research in 1976 at a time when we were spending as a nation billions of dollars on the war on heart disease and the war on cancer and we spent six hundred and twenty five thousand dollars on alzheimer's research and and i say these historical things because alzheimer's research started really in the early 1980s um which was i guess about 40 years ago that's not a long time in the history of research for a disease the beta amyloid protein that everyone knows about plaques and tangles and all the proteins today that are in those plaques and tangles that wasn't discovered until 1984 and the gene discovered in 1986 and around the same time a molecule called tau was discovered in the dying neurons in the tangles today just this past year in the last few months you heard about biogen's drug uh and how there's a lot of controversy about how the drug came about to get an fda approval but the fact is the drug worked and it's really a breakthrough and i just want to tell a quick story before i turn this over to frank um and it's it's kind of a story of of not only what happened in my professional career but what the foundation was able to do a small foundation at the time to make a huge contribution to the field so in 19 in 1999 somebody called me up from the university of pennsylvania and said i have a crazy idea and i can't get any money for it and i said what's that and he said i want to take the same dye that alzheimer used in 1906 to stain the brain of that 52 year old woman and discover alzheimer's disease the plaques and tangles and i want to put a radial label on it and i want to be able to inject it into the artery of a patient it'll go up into the brain it'll bind to the plaques if it's there and it'll show up on a simple pet scan and the beauty of it is that we won't have to do an autopsy to make a definitive diagnosis of alzheimer's disease we'll be able to do it with a brain scan and so adtf started funding that program from 2000 to 2004 at the university of pennsylvania in 2005 the the program was spun out into a small biotech company called avid radio pharmaceuticals with about seven million dollars in venture capital in 2010 that company was acquired by eli lilly for 800 million dollars in milestone payments of which we got royalties on and in 2012 that test became the first first test approved by the fda for the diagnosis of alzheimer's disease and today if somebody comes into my office with memory problems and they want to know definitively if they have alzheimer's disease i can send them down the block to the radiology office and by the next day i can tell them whether or not they have alzheimer's disease now that really has changed to some degree clinical care it's expensive and it's not paid for by medicare but what it really did is if you heard about this recent drug from biogen the drug got what's called an accelerated approval which means that the drug had a pharmacology to remove the amyloid from the brain and test the theory that if you could remove the amyloid from the brain you'd slow down the disease now how are scientists going to be able to see if you remove the amyloid from the brain they used our test everyone who went into that clinical trial for the first time had to have a positive scan that was a big advance and then the people were administered the drug and the test was used to see if the drug was working well the drug worked and 80 percent of people that got the drug at 18 months their brains was completely cleared of amyloid we could tell from the brain scan and not only that but their tau biomarkers got better so we know that that drug works because of the biomarkers and there's a signal there that it looks like the disease is slowed down this is in in my opinion although the drug might not be clinically useful at this point the drug got an approval based on the the biomarker test there is also a blood test on the market now in 49 states not in new york but in 49 states you can go to your doctor and get a blood test and find out if you have alzheimer's disease we've invested in that for over 10 years i tell you this because in conclusion let me just say that we have we're funding over 30 clinical trials in different areas of as mark mentioned inflammation and so on um but what's exciting is that we haven't had a drug approval in over 20 years in alzheimer's space we've had failure after failure after failure but the field has matured from nothing i mean literally nothing 40 45 years ago to where we're in a really exciting time we have biomarkers we can we can see if a drug is working we can subset patients according to their profiles and we can test drugs there's over 100 drugs in clinical trials and many of these are not the amyloid drugs that you're hearing about from biogen and lily and rose these are in all different areas of research as mark mentioned we're aging is the leading risk factor for alzheimer's disease and there are these various pathways that the cell goes through that's why cancer is a disease of aging and people with cancer need to be on four or five drugs to attack all the pathways to conquer the cancer people with diabetes are on three four drugs people with hypertension we're going to have the same thing with alzheimer's but we've made that first step i really believe we have the first step now the thing i'm most excited about and we've been doing this for over 20 years is working with frank longo and i'll tell you why because brain cells can get injured many different ways they're being bombarded every day and through evolution brain cells and other cells in our body have developed protective mechanisms to survive and fight all these different ways the brain can be injured well there are hormones in the brain one's called ngf and the other is bdnf and frank's going to tell us about that which kind of say to the cell regardless of the form of injury we're going to activate these signals that protect the cell from dying or if the damage is so bad the cells go in and basically commit suicide to get out of the way and i'll let frank tell you why this is so exciting but this drug could really be revolutionary and we started working with frank on this back in the year 2000 frank is a profes is the chairman of neurology and neuroscience at stamp at stanford university medical center prior to that he was chairman of neurology at the university of north carolina and chapel hill and before that he was at ucsf and we've been working with them all through that period of the last 20 years um and helped him start a biotech company and um it's just been a fascinating journey to work with frank so frank maybe you could start us off by telling us how the project got started and and and what it's like to develop a drug and also i want to say that frank being chairman of neurology and neuroscience the co-founder of a biotech company and a leader in drug development he's he's a classic physician scientist i mean we we all really respect frank for what he's doing and brings the whole whole nine yards to this effort well thank you howard um and i also wanted to add my welcome to everybody thank you for being here it's been a pleasure to work with howard and his team and the addf over the the years and appreciate the lauder family support and all the other supporters here so thank you um so howard you know your question how we got started i've been interested in the brain for a long time in the biology of the brain i've been interested in regeneration um when i was younger i was told that there could be no treatment for a brain injury or brain disease and so once i was told that then that i set that as my life goal is to make therapies for the brain and right before i met howard we had noticed in alzheimer's disease that it seemed like there were mechanisms in alzheimer's where the brain started degenerating losing the connections between neurons that were similar to how the brain is built in the first place and how the brain's wired in the first place and so we had an idea of creating therapies that would harness those very powerful mechanisms to protect the brain and i can share more details with that but to make a long story short i applied to nih for a grant to pursue this and nih has to be fairly conservative about what they'll fund and that at this time about 20 years ago there was a lot of excitement emerging about amyloid as howard mentioned the amyloid accumulates in the brain and alzheimer's and people were coming starting to come up with therapies that might be able to lower the amyloid so that's what was exciting so when i applied to nih for a therapy approach that did not involve lowering amyloid they thought it was pretty interesting but not quite in the fundable range and so next thing i knew i got one of the best phone calls i ever got from howard phillip he can tell you about that but introducing me to addf in a possible way to get this new area funded so frank frank was trying the way you start out is you try to get molecules right that's how you develop a drug i mean it's so complicated it's unbelievable imagine you're trying to develop a little white pill that's going to cure alzheimer's i mean and 90 percent of people that work in the pharmaceutical industry spend their entire careers never working on a drug that comes to market 90 percent because it's so hard and failure is the norm but people love science we love the process of science and um what frank was doing to develop his drug was the very beginning so he he bought a computer library uh maybe you could tell us about it i can tell you about how we got started so there are naturally occurring proteins in the brain that dictate whether a connection between the neurons will be maintained so when our brain develops we actually have more nerve cells and more connections that we need two or three times more and so then then there's what's called a pruning process like pruning a tree where we get rid of many of these connections so the brain works better and so there are mechanisms inside the nerve cells that really carefully control whether a connection between the nerve cells will persist or not and there are some naturally occurring proteins that are very powerful regulators of this process howard mentioned them once called nerve growth factor or ngf and the other one's called brain derived neurotrophic factor or bdnf these are two very powerful proteins that dictate keeping a synapse or not and in fact the discovery of these powerful proteins uh was done by a scientist named rita levy maltochini an italian scientist and she won the nobel prize in 1986 for the discovery of these very powerful brain proteins and when she gave her nobel prize acceptance speech one of her main remarks that i noticed was well it's great that we discovered these proteins i hope someday in the future somebody will figure out how to make a drug out of these proteins because a protein itself can't be a drug for the brain it's too big to get through the blood-brain barrier so it can't be used for a drug itself so what we wanted to do is create drug-like compounds or small molecules we call them that could be just as powerful as these naturally occurring proteins and do what they do to tell the neurons to maintain their synaptic connection and to protect those neurons against whatever might come along whether it's amyloid or tau or inflammation we thought these drugs could protect the neurons against those things so we set out to find and make drugs that do what these proteins do and the old-fashioned way of doing that is you could test physically thousands and thousands of compounds to see if they would have the activity that these naturally proteins do and this could take 10 or 20 or 30 years this could go on forever and nobody would want to fund that so i i brought in a friend of mine that's a software and computer genius much smarter than i am steve massa and he and i figured out how to use this software to screen uh drug libraries on the computer for hundreds of thousands of compounds every day and we ended up finding these small molecule compounds drug type that have the exact same shape of the critical part of these powerful proteins and so we were able to obtain these we hired medicinal chemists to work on them further and we discovered that they we found a few that have very powerful ability to protect neurons from dying and then the next step was to move into the mice so it's a long process but that's how we got started right so what took a year of funding from us you say can be done in about a week now i think you tell me yeah the good news is it was what we spent a lot of time doing all these technologies have improved and this can be done much faster now more efficiently right so so we went from the chemistry you screened about two million compounds as i remember and out of that 2 million you found about 60 that looked pretty good you bought the powders from a company that sells the chemicals and then you tested them in test tubes to see if the powders fro of those chemicals protected cells from amyloid injury and then you found two out of those 60 that protected well enough that you went into mice that had alzheimer's engineered into them right and this so now we're going from like the year 2000 to probably 2010 2015. that's right but along the way while you were at unc you and i were talking and this was really exciting and i said to you frank why don't we start a biotech company and so you did and yeah so at that point we had uh one and several backup compounds working in alzheimer's mice and that was really exciting and you could build your whole career on just that you publish a paper saying the compounds work in mice and that these could be a treatment for alzheimer's someday you get promoted to full professor and that's it but we were determined to get these into people and now it starts to now the hard work really starts how do you go from a mouse to a person and i could see that it would be very difficult to do this in a university laboratory environment you mean the university laboratory is great for a lot of things but moving something into a commercial or clinical part is much more difficult and we were too early to hand this over to to a pharma company at this point it would have been too risky for for our friends in pharma so the only option left was start your own company license it to your own company of course i had no idea how to start a company and and that's where howard and the addf were very encouraging frank if you start a company we can fund it so wow okay um so i i found an attorney and in one day the initial name of our company was longo pharmaceuticals um and uh but then the university said they wouldn't license the technology to long ago pharmaceuticals unless we had funding and so the our first funding came from addf and then the whole thing could get started that way so so we've been we were first investors and we've continued to invest along the way and it's now almost 15 years later and the compounds worked in mice which is pretty amazing and then you got into the regulatory science which is a whole nother thing like what you have to do to take a molecule and be able to give it to human beings with all the fda regulations prove its safety and then go into phase one and that's a that was a whole nother thing yeah moving from mice to people involves a lot of safety which is good um so the um fda requires that a a new drug is first undergoes additional animal testing um in rats and other animals i mean it's all i think done very respectfully to the animals i learned a lot about it and fortunately all of that and this took two or three years all of that animal testing was very safe the animals did well in our drug and they're monitored very carefully and i learned about how important this is how challenging it is and for an academic person um it's not exciting you don't publish a famous paper because your drug was safe in iraq um but yet it's so critical before we we move to people right so all that went well and then it was time to meet with the fda uh to see if we could get permission to start our first human study now because our drug was entirely a new category new class of drug and the target we were going after in the brain with this drug nobody had ever gone after before the fda required that our very first trials would have to be in so-called normal people not not alzheimer's patients but normal people so that was a a new area then we had to get funded what's called a phase one trial phase one in normal people uh just for safety so that was the the the next step that i can tell you about but each there are different chapters along the story here yeah well the most exciting thing is that uh after proving that the drug was safe for the first time and we're talking like 15 20 years later um and and by the way during this time franks of practicing dr frank's chairman of neurology and neuroscience at stanford i mean i i don't know how you do it but yeah not much sleep um so the the very first time this dr our drug our lead drug we're developing many drugs uh was given to a person was a very emotional experience for me um how how this is done there are companies that help with the first test in humans and so this particular company was a well-established company in kansas called pra and so uh people volunteer to be first to take a drug and so we had 72 normal volunteers in our phase one trial younger people and older people all you know fairly none of us are perfectly normal but all fairly normal people you know nobody had alzheimer's in this group at that point and so um the the volunteers uh come in uh they stay for 10 days in an inpatient type of setting where they're monitored 24 7 by doctors and nurses and our our drug unfortunately is a capsule you take it by mouth it's not not an intravenous um it's a capsule um so the the very so i got to be there i wasn't directly involved but i got to be there and watch everything so the very first uh person to take our drug was a a gentleman in his 20s young guy and when you first take the drug they put in a paper cup they give you a glass of water you've got nurses and doctors there you've got an ekg on your blood pressure's being monitored they're going to be taking your blood they're monitoring everything no human being has ever taken this drug before and of course for me i'm a physician the first rule do no harm at this point i just didn't want anyone to get hurt taking this very new drug that we had invented and so he put the capsule in his mouth and he took the glass of water and swallowed it and believe it or not they made him open his mouth and with the flashlight they look and see if he swallowed it and so he did and then they start measuring his blood pressure and everything and you know fortunately everything was fine blood pressure the vital signs the blood tests were all okay and they were for everybody else and afterwards i got a chance to talk to him and i said what made you volunteer to take this drug you don't even have any medical problems you know this this could be dangerous i mean usually it's not if it's safe in rats and dogs and he said to me you know dr longo my grandfather raised me and he died with alzheimer's and it's the least i could do and it just it just really shook me up with that what that meant so this is a team effort from him and all of us as well so frank you you recently did the phase ii trial and a few hundred people i think in europe and um reported that results of that trial of this what i think is a revolutionary drug which would be good not just for alzheimer's but other neurodegenerative diseases potentially parkinson's and others and you reported on your results in boston uh i guess a couple months ago um where we actually looked at whether the drug works and that was that's probably the most exciting thing that you're going to tell us about because i think you did get some positive results but we still have challenges so tell us about that yeah so that i described the phase one trial for safety in normal people phase two is the first time in alzheimer's patients um at a smaller scale and then the phase three would hopefully be the last trial so howard's uh described that we just finished phase two in alzheimer's patients at the mild to moderate stage so we decided to do a trial with people in the mild to moderate you know somewhat more advanced stage than what many of the trials are many of the alzheimer trials nowadays are much earlier stages as you probably know but what we were finding in our alzheimer's mice is that we treated some of the mice at late stages on purpose why did we do that we really think this drug has a very strong biologic effect and what we were seeing in the late stage alzheimer's mice is some reversal of the loss of synaptic connections so you'll always hear that oh we have to treat early this can only be prevented that's the only solution i don't agree with that i think if the biology of the drug is powerful enough what we're seeing in the mice there's some reversal component too so we wanted to go later stage in people to really find out how powerful can this drug do something in a later stage person because if it can do something there it's going to be even better in early stage so mild to moderate later stage and 241 subjects one-third of them on placebo one-third low-dose and one-third high dose you know blind to trial nobody knew what they were on or the neurologist evaluating them didn't know we treated them for six months and that's a limited time frame but that's as far as we could go in a phase two trial the first time you're in the disease now for phase three we'll treat for 18 months a longer period and our question we had two questions was it safe in alzheimer's people and number two did we see any evidence for slowing down the progression that we would expect to occur even over a six-month period unfortunately for most people mild to moderate alzheimer's even over six months or some progression and we measured the progression using three techniques um an mri brain scan looking for parts of the brain that shrink over those six months what we call an fdg pet scan that measures metabolic function in the brain and measures how well those synaptic connections are are communicating with each other and then we did a spinal tap looking in the spinal fluid for proteins that go up with degeneration so the more degeneration there is the more these proteins go up as the neurons are degenerating in all three of those areas mri brain scan fdg pet scan of the brain and then the spinal fluid uh proteins in all three areas we found evidence that our drug was significantly slowing down the degeneration during that six months compared to the patients that were on the placebo and this is really exciting one of the the top people in the world that measures those spinal fluid proteins his name is kai blenow he's in sweden in fact he did the the studies for us but he was blinded he did he didn't know when we unblinded the results for him and we we had a zoom meeting uh with him he said he thought it was remarkable he hadn't seen any therapy have this effect on those spinal fluid proteins uh like like this before so we're really excited about that and then the the pet scans of the brain were done by eric reiman one of the top people in the world in pet scans he's in arizona and we provided to eric all of our raw data like it's not interpreted by us we just gave him all the raw pet scan data he came back to us saying frank there's a significant effect on drug versus placebo on on this brain scan so anyway good news from that phase two trial and now our goal is to move on to a phase three trial that will be much larger so frank um just give people a perspective how much did the phase two cost and how much would how much money would you have to raise to do the definitive phase three trial i i mean i i obviously know the answer but yeah yeah the phase ii trial cost probably a total of close to 20 million dollars and um and so that was obtained uh partly from private investors in our company and partly from nih and partly from addf so in each phase we always involve peer-reviewed funding um so that a third-party experts are are evaluating our technology it's it's not my opinion on our technology we always have a third party peer review and so now the phase three trial they they'll they'll have something like 1500 people so much larger so now we're talking 200 million dollars 250 million dollars you know a lot more expensive but there are options to fund that uh it could be a pharma partnership uh nih could fund it or you know some of our investors say they can raise that amount so you know we'll fund it one way or the other so i i just thought you might find it interesting to hear the journey of a scientist over 20 years to try to develop a drug out of an academic setting into a biotechnology company with really novel technology that really could be revolutionary because of its mechanism of action this is a pill it's not an infusion it could be widely used not only for alzheimer's in multiple populations but for other neurodegenerative diseases and we're right at the point now after frank's done this for 20 years and we've been investing with him every step along the way so it's an example also of how venture philanthropy can really play a role in in a high risk program to keep the program going to provide the validation from the addf as a non-profit so that other investors take advantage of our due diligence and say well we know addf does that kind of due diligence and if they vetted it then we're we're more comfortable making investments in that as well um and and and the journey's not over and obviously there's there's still a chance for failure here but i think the most exciting time for frank's uh technology in the phase three and so many others we have so many other drugs now in this phase three stage um that we don't have time to talk about unless you want to ask questions about them um that that i really it's just such an exciting time we have the diagnostic biomarkers to use as frank said the main outcome of his phase 2 trial was to show that the drug actually did something because it moved these biomarkers so we know the pharmacology works and to get the effect on on the clinical outcomes takes a much larger study that's basically the fact that to see a change in cognition you need more people so um maybe with that mark i see you're they're there and we're a little over time maybe no um well i i just wanted to say one more thing if i may so frank mentioned earlier on that he's also has another class of agents in development which are probably more powerful and more neuroprotective it's called bdnf and one of the things that's really interesting in my view about bdnf is that we know for a fact now that exercise prevents alzheimer's disease to a certain degree we know that i mean i think after 20 years of work that we've funded in others we can say that exercise really delays the onset of alzheimer's and even with in people with alzheimer's who exercise their cognition gets actually better the question is how does this work and there's many proposals about various hormones that are released during exercise it's not just the blood flow effect but this bdnf that frank is developing is one of the hormones that's released during exercise that goes up into the brain is very powerful in creating new synapses but the problem is frank said is it's it's not understanding the biology that's the problem it's creating the drug the real challenge is in the drug is the making a drug out of something you can discover a gene but to make a drug out of a gene is really really hard it's much harder than discovering the gene so in this case what frank is taking is the same strategy of taking this big molecule this big molecule that can't be delivered it can't be really manufactured very easily practically as a commercial product and knocking down that big molecule into a small little pill with small molecules that could be taken early that would mimic the effects of bdnf so we're funding that at the company also maybe you could tell us a little bit about that and then we'll let mark in and uh take over sure that's the area of this bdnf brain derived neutral factor very powerful supporting these connections they're helping us make new connections and the naturally occurring protein goes down as we age it really goes down with alzheimer's disease and other neurologic diseases so we've made several drug versions of this successfully uh they're working well in many different forms of alzheimer's and other mice including parkinson's mice we're too excited about and we're at the point now we're ready to do the testing that will move our best candidate into humans so our goal is to replicate what we've successfully done with the first category and get this into to humans as well and as when i presented this uh program to our board one of our board members said well when we were talking about the fact that exercise improves cognition it prevents brain atrophy as a biomarker and he said well you know exercise is great to prevent brain atrophy and it'll slow down my loss of memory but can't you invent a little white pill that i can take because i'm a couch potato and i said yeah we got a program like that so with that i want to turn it over to questions uh right we're going to take some questions in a second and just don't worry when this is done we're going to be serving hot cocoa so you'll be all warmed up i will say also just a perspective for a second frank is one of 35 clinical trials that howard and the addf for funding right now and to the very point that howard made and frank is it's more than five years ago is it ten years ago now there was a front uh uh page uh front cover article in time magazine when we used to buy it and hold it in our hands and said imagine the day when a single pill can cure alzheimer's they were talking about frank and you just heard where it is today so 2016. there you go 2016 which is great okay so um dr phil what uh give us some more information about exercise how much how often is it do i have time tonight to well i think there's two ways of looking at it the the research that we funded um i'll give you an example of the kind of work that's been done this this came out of a walk i took with somebody in the arizona dentist where we did a meeting at canyon ranch and we thought about how we could look at this so basically the study design was very simple we took about 50 75 year olds to his this person's physio sports physiology center at the university of indiana and they came in three times a week they did a 45 minute walk you know a brisk walk but nothing fancy they did stretching and socialization and they went home and the control group came in and did the stretching and the socialization but they didn't take the walk we did that for six months at the beginning of the study we did neuropsychological examinations and we did brain mris and then at the end of the study it was it was very inexpensive study we did repeated the brain mri and the neuropsych now the normal brain shrinks at an annual rate over the age of fifty of about point four point four percent a year and in alzheimer's it's about four percent particularly the area of the brain that's responsible for memory and learning called the hippocampus the people who didn't take that three times a week 45 minute walk their brains shrunk at 0.4 percent a year and their memory scores declined according to what would be called normal aging but the people who took the walk their brains actually the hippocampus got bigger and their memory performance improved now that's been taken out to if anybody knows when lance armstrong or these tour de france they're measuring their vo2 max which is the efficiency with which their muscles use oxygen which is a reflection of how fit they are and we did a study using vo2 max as a continuous variable along with bdnf in the blood and some other biomarkers to try to understand the phenomenon to understand the biology and it turned out that there was a direct almost straight line correlation between vo2 max in other words fitness and the rate of decline on the on brain scan and the the rate of decline in memory in other words the improvement it kind of peaked at a certain amount so we don't want we're not telling people to go out there and be crazy but there is a continuum of doing more is better and the same was true for bdnf so what the current recommendation is from the cdc and places like that which we've talked a lot about lately cdc recommendations but the cdc recommendation is about 150 minutes a week and whether that's basically a brisk walk but if you want to run if you want to do the elliptical it doesn't matter um just there i just read a recent study that's it the really bad thing to do is have sedentary life because that's really bad for you and anybody who's sat around all day feels groggy and i think that's very real anybody that has depression who exercises feels better and that's very real that's biological so we know in our hearts we know from our personal experience that exercise fit affects our brain and we now know from the biology um that that's true but what we'd really like to know is how it works so we could develop a pill that would mimic that and enhance all everyone's everyone's lives studies done in terms of lifestyle factors and they have really proven definitive but are you then doing any studies that in addition to the exercise factor in um you know eating habits you know they promote the mediterranean you know diet and um wait you know weight control and that kind of thing so i'm wondering if you're kind of you know having like a b c or d and and then measuring kind of if you can maximize by incorporating these other elements well one of our recent board members is a friend of mine named mia kivapelto from um helsinki finland that's right i got that right and she is a world leader in this prevention research she's done the only randomized controlled trial of prevention and showed that prevention works so there are like 12 factors as you mentioned obesity sleep stress diet mediterranean diet exercise don't smoke don't drink too much alcohol manage your diabetes manage your hypertension wear your hearing aids these have these 12 have all been validated by something called the lancet commission in the uk that if you do all those things people who would do all those things could reduce their risk of alzheimer's disease by 40 percent that's huge that's more than these drugs do so mia's study has is being replicated in every major country throughout the world now to see in different populations if you do prevention if you do all the things that you're supposed to do can you slow down cognitive aging and prevent alzheimer's and the the what we call implementation science of her of her work is that the control group just got education and counseling it's like you go to the doctor and the doctor gives you a piece of paper and says here's what you should do go home and read this and do it versus a program where there's an intervention and you're kept to be compliant and that was the randomized trial what we're doing if you think about how we prevent heart disease we do all these things what's good for your heart is good for your brain but we add statins because we know cholesterol is a risk factor so we can have a medical intervention that's preventative along with these lifestyle risk factors what we're doing is funding mia to add metformin to her lifestyle intervention program because metformin has we've run clinical trials of metformin which is the leading diabetes drug but it's also been shown to improve the metabolism of the brain um and so there's a lot of interest in using metformin for alzheimer's in a repurposing manner so we're using metformin in people who are normal cognitively normal but they get the brain scan so these are people that have alzheimer's disease but they're not symptomatic yet and the purpose of the trial is to use lifestyle interventions with comorbidity management of diabetes and hypertension because they're risk factors along with an anti-aging drug and see if we can really have a big impact on preventing cognitive decline and preventing the accumulation of the amyloid in people that don't have symptoms yet because that's ultimately would be the goal right to prevent people having symptoms uh are there populations on the planet that have more likelihood of getting alzheimer's in populations that have less less likely to get it yeah i mean that's a good question are there populations or people that are higher or lower risk for alzheimer's probably not intrinsically genetically i think it's more the different populations having different lifestyles um that would you know people that as part of their living situation are getting more exercise or eating in a more healthy way you might see lower rates of it but i think in terms of um you know just genetic propensity i think every you know just about everybody's at risk yeah i mean the japanese tend to get more vascular dementia which is the second most common cause of dementia the vascular disease of the brain but i think another way to look at it is um african americans are more at risk and it doesn't look like it's necessarily related to socioeconomic status hispanics are more at risk and again it's not clear why so there's some diversity issues here and women are more at risk so we don't exactly know why and again it's it's how do you do prevention studies that's the really interesting question because you know when women are more at risk at age 75 how do we find out what it was during the course of a lifetime that caused that increased risk well the one thing we know about women that's different from men is women experience the menopause and at the time of the menopause there's dramatic decline in estrogen estrogen like bdnf like nerve growth factor is what's called a neurotrophic hormone in other words it's neuroprotective in the brain there are estrogen receptors in the brain in men and women actually um and these are these trigger signals in the cell that are protective so when um and 60 to 70 percent of women at the time of menopause complain of memory difficulties and emotional irritability a whole host of psychological symptoms for most women that goes away so this really interesting study that was done recently by lisa moscone at weill cornell and one of our board members from the university of arizona they took these brain scans that i've been talking about the amyloid brain scans that we invented helped to invent a pen that's been used so many times and and and looked at women at the time of menopause and said gee i wonder when women get this dramatic drop of estrogen at the time of menopause is it bad for your brain so they did amyloid scans the amyloid scans and what turned out is that women who didn't take any hormone therapy they started depositing amyloid during their menopause you could see it on the brain scan the women who took premarine there was no difference but the women who took 17 beta estradiol which is the naturally occurring hormone that women produce and what is lost during the menopause the women who took 17 beta estradiol did not accumulate amyloid during their menopause period so this tells us that there is something happening during the menopause that starts a process that ends up as dementia 20 years later and could be the risk factor for um for why women are great at risk and the analogy here that you probably all understand is osteoporosis in fact the whole brain thing came out of the model of osteoporosis there's a window of opportunity to prevent osteoporosis at the time of menopause by giving estrogen replacement therapy but if you let that wind to pass if a woman doesn't take the estrogen at 51 and even tries to start taking it at 56 or 60. the horse is out of the bond the osteoporosis has already started but if women take it at the menopause at 51 the osteoporosis can be prevented so it's the same sort of way of looking at how we can do prevention studies and ultimately design better therapies just two quick questions um do you support the protocol that dr president gives in his book the end of alzheimer's that's number one and the second part is what is your feelings on the faux bio-modulation caps you know the via light that people now are using and can used they think to target the tao yeah two good questions you know so dale bredesen's book so i know i know dale we were both at ucsf at the same time and what his book talks about is going after all the factors we could possibly go after diet sleep vitamins everything and the reason why it's somewhat controversial is because he hasn't been able to really do a controlled trial you mean the claim is that people's cognition is actually improved when they're in early stages of alzheimer's or mild cognitive impairment so that's a big claim to make that cognition got better but there's been no trial so the concepts make sense that doing all that is helpful most of us agree that sleep and mediterranean diet is helpful but there's no data so you know so i think people like howard and i encourage those things anyway i think dale bredesen's book is just an extreme of that um and then you asked about the stimulation caps yeah so there's two areas one's called transcranial magnetic stimulation and then there's a more recent one 40 hertz stimulation i don't know if your which one you're asking about i can comment on both the transcranial magnetic stimulations putting magnets around the head and the brain gets some kind of magnetic stimulation and this is currently one form of this or many forms is currently approved for depression treatment by the fda so psychiatrists use this there's been in studies for at least 10 years in alzheimer's and not no consistent results so that's why you you don't see us jumping into it i think more work needs to be done there's the more recent 40 hertz stimulation that was started by a group at mit that's been in the news more recently so a little bit more recent in in the alzheimer's mice it shows uh some changes in in brain function which is encouraging um a phase an early phase trial in human alzheimer's is just near uh wrapping up it it's a complex mixture that they're seeing some aspects of inflammation are increased with the idea this might remove some amyloid so it's it's not something i would do outside of a trial because you know we're seeing some increase in inflammation maybe some removal from amyloid you can buy these 40 hertz things on amazon but i recommend to my families just you know wait another year or two to really see what the formal results of a trial are is that i think that's part of your question what about the brain mapping oh yeah i think just mapping the brain is fine just to observe you know there are these clinics that claim all kinds of brain imaging and brain mapping um there's there's one that's pretty well known um but it's not really rigorous um and so you know you could ask me more about that i have to be careful what i who i comment publicly but a lot of this stuff is just marketing and i'll just add um in terms of what dr brennerson is recommending that several of the things he recommends are supplements ashwagandha for example and we about 15 years ago developed a website called cognitivevitalityoneword.org last year we had 1.4 million visitors and we have three full-time phd scientists at the foundation um sponsored by a private donor who are writing reports on these things their technical reports on the on the website and then there are reports that are friendly for laypersons so ashwagandha and bacopa and these other supplements that are commonly used i mean i get patients coming in with a suitcase full of you know they're on 30 different things and we don't know what's in these things we don't know if it's poisons in these we don't know how much good stuff is in them there's no not really proof so if you're really interested in seeing what he's recommending and what our scientists are rating these on in terms of safety and efficacy this website is cognitivevitality.org thank you howard excuse me so what what are you going to tell women my age who when we were going through menopause we were told don't take estrogen replacement therapy that it was not good for you yeah um you know there is controversy about taking estrogen starting estrogen after the menopause i mean there are there's i know people who have done it and there was one study the women's health initiative that enrolled over a hundred thousand women and studied the impact of estrogen replacement therapy in postmenopausal women so the average age of the women in that trial was 65. and although the trial has been cr was criticized what it showed contrary to what we thought which would be that getting taking estrogen at 65 would be protective and all that that taking estrogen at 65 actually increased the risk of stroke and dementia and even heart disease rather than decreasing the risk so unless there are other symptoms of menopause like hot flashes or vaginal dryness or things like that sleep disorders that are related to that um personally i i don't think most gynecologists these days would be recommending estrogen replacement for women that are many years post menopause doctor um have you now or are you planning to do any experiments with cbd or cannabis so cbd is really interesting and the pharmaceutical industry has tried so so in the brain in the normal brain there's two types of cannibinoid receptors there's a cb1 and a cb2 and the cb1 is the psychotropic receptor so you take thc and it goes to cb1 and gives you all the highs and everything cb2 is actually an inflammatory receptor and you know we know that cannabinoids they're being sold as anti-inflammatories well in the brain there's a cb2 receptor that is neuroprotective actually when it's triggered by thc uh and other cannabinoids what we're doing is we're funding the um case western reserve we spun out a biotech company there called neurotherapy and they have small molecules that don't have the psychotropic effects of cb1 activation they only have the the small molecules have been engineered and designed through medicinal chemistry to have the cb2 activity and that program is now in phase one and hopefully it will soon raise enough money to go into phase two and see if that cb2 receptor drug can be used to treat alzheimer's disease one cannot watch television for 20 minutes without finding an ad for some brain-enhancing supplement or drug uh you mentioned something i think about an anti-aging drug is there any such thing and it's any of these things that are totally on television all the time are any of them culture i i have i have a i have a uh i have a a shelf in my office in my bookshelf of like about 50 different supplements that you know are being sold in dwayne reed and cvs and i always look at what it is and it's often like things like phosphatidyl phosphatidylserine that was proven not to do anything like 25 years ago and things like that i mean the most common one you see is prevagen right and but what i'd encourage you to do is as the commercial comes on in very light white uh lettering it's so small you can't see it and it says what the drug the fda requires them to do honest marketing and it says what the drug actually did in clinical trials and it you know if you look at the data there's like no data basically so they're allowed to sell supplements as long as they don't make claims that's the that's the thing about the supplement industry it's a 10 billion dollar industry because these supplement makers are allowed to make claim allowed to sell supplements as long as they're safe and they don't make any claims and basically prevagen they can have testimonials but you'll see that they're not really making any disease claims and if you look at the actual the you got to catch it because it's only on for a second it's almost not readable you'll see that it doesn't too much well the metformin there are several we're testing some other drugs some analytics that what drugs that are called centalytics at wake forest um but the metformin is one of the more interesting ones these days i would say that's available it's a diabetes drug but it can be prescribed off label and it's basically safe i i do prescribe off label um and for for people that i feel it would be safe for i'll prescribe a low dose and try to explain benefits and possible harms particularly people that have mild memory problems and they want to do something and i i feel that i am willing to prescribe them something based on what i think is good science even though it's not definitive okay yeah thank you both so much um for this really informative and just enlightening conversation tonight i'm really curious about the digital biomarkers and digital therapeutics that are coming out and what areas you see as most promising for alzheimer's and dementia research moving forward i i think i can yeah well as as many of you may know we we have now almost 100 million dollar initiative with bill gates with gates ventures with jeff bezos with mackenzie scott with david dolby with the schwab foundation with the association anyway i won't go through all of them um and the whole purpose is to develop digital um one of the main purposes is to develop better diagnostics and protect particularly digital technology so let me give you one vignette of how did i see digital technology in the future one of the earliest signs that someone can pick up a spouse can pick up or a friend or even during a speech is a change in language you know people have word finding difficulties their grammar sort of changes their intonation changes over the course of speech gets a little flatter um and you kind of you know people lay people when you hear that you kind of sense like it's not quite right well it turns out that with all this new speech technology you can pick that up and analyze it with artificial intelligence and so it means that we can diagnose alzheimer's disease way earlier using speech and language technology then we can you know when we don't have to wait for someone to come in where the spouse says he keeps asking me the same thing 10 times in an hour and so how do you distribute that technology is it going to be on a cell phone is it going to be on your computer will be monitoring people as they use the computer will it be a passive collection of data in other words people will be connected through their apple watch and somebody will be capturing the data over time or will it be active like you you'll sign in once a month and do it and we'll get some speech patterns from you the other thing in terms of that's early diagnosis is how we'll use that technology in clinical trials because it's very sensitive and it's an important clinical outcome knowing what how people's speech is changing so it could be an additive outcome measure in clinical trials as well to see if a drug is working and we're very excited about that and there's many other types of digital technologies like right now most doctors are using paper and pencil tests and we're converting a lot of those paper and pencil tests into much more sensitive digital tools that can be done on an ipad and will give doctors much more objective measurements of cognitive function in the office at a very low cost that's good um first of all can we have some applause for our wonderful not just real brilliant brilliant presentation you know the last question was a perfect one to end on because at addf three things and you heard them all tonight preventions biomarkers and we heard why that's important in treatments like you heard about tonight um three final words your thoughts here one um you all can find uh at your sea place uh save the date for our hope on the horizon dinner taking place on march 3rd at the beach club i will tell you howard mentioned another doctor dr mia kivapelto the leading doctor of prevention in the world will be with us that evening so worth coming out and seeing second after that on april 26th we'll have our final in this year's series lecture series and we'll feature another one of our clinical trials dr jeffrey cummings from the university of nevada and again there's information at the table as you leave on that and last but not least for all of you who still have questions the two docs aren't just going anywhere just yet the bar is open in the back i don't know if there's hot chocolate there and up but there's liquor okay thank you for being with us tonight

Channel: Alzheimer's Drug Discovery Foundation

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Id: b9x20zjXuPw

Length: 66min 23sec (3983 seconds)

Published: Tue Feb 08 2022