Hope on the Horizon Palm Beach Symposium

welcome everyone to the addf hope on the horizon science symposium i am mark ruthmar i have the privilege of serving as the ceo of the alzheimer's drug discovery foundation first of all how fabulous is it to be back together again and do several people in this room the last time the addf did a live event we were actually in this room and two years later almost to the date we're back together again it's been a long wait but we're together and as the name says there's not only hope on the horizon but hope is starting to deliver and you're going to hear all about that tonight i will say for those of us who are in this room two years ago there was our wonderful and i'm going to give an official introduction in a minute dr howard phillip he was joined on the right of him by dr ron crystal who was talking about a new investment the addf had made into a trial for gene therapy in alzheimer's take the bad gene out for alzheimer's put the good gene in and literally we just heard this week the first reports out from their phase one trial that literally if you were here two weeks two years ago you helped fund that clinical trial and not only that it was safe but the science was showing some really interesting engagement of what that might mean for bettering cognition so here we are two years later three areas of alzheimer's science that the addf invests in one the clinical trials i just talked about two diagnostics and biomarkers and that is a wonderful affiliation we have with bill gates and jeff bezos and mackenzie scott it is a hundred million dollar effort that they're helping to fund for us along with the lauter family and it is an endeavor that with the history of dr howard's phillips funding we've seen the first pet scan that can diagnose alzheimer's two years ago the first blood test that can tell you and we were on the verge of something that recently got fast tracked by the fda that we're funding that will be the first digital biomarker using artificial intelligence so we're at a point now that we can diagnose the other part of our mission the three parts the clinical trials the diagnostic biomarkers is prevention and if you even go back five years ago there were things you talked about you could do that might slow it down or put it off but in the last three to four years now we scientifically know what can be done in prevention and you're going to hear about that tonight so i'm going to turn this over now to dr howard phillip and most many if not all know in the room but howard i'm going to do it anyway 25 years ago the water family came to howard asked him to be a co-founder of the alzheimer's drug discovery foundation the uniqueness of that foundation was one because of the generosity of the lauters they cover all the overhead so if you make a nickel donation that nickel goes directly to the science number two the foundation would not make grants to academics or to biotechs the foundation would make investments a contract between the donations that come from you to that academic institution or to that biotech so that if they see any promise hope deal flow come out of that addf gets a portion of that money back which we put right back into the science again okay and 25 years ago they tapped howard on the shoulder they said howard what do you think of this idea because oh that's a great idea and i don't think you were ready for the second tap howard that said and howard would you be the first employee ever would you co-found this with us and will you start this foundation 25 years ago but howard because you see he's so young in sprite physician scientists over 40 years working on this and i can assure you because we at the staff get to work with him day in and day out he has one true north what can he do for patients so ladies and gentlemen i give you to lead us through our symposium today dr howard phillip co-founder visionary and a pretty darn good friend too thank you [Music] oh thanks mark and i want to thank everybody for joining us today i hope we'll have an interesting session and we really welcome your questions we're really here to answer your questions i'm here with my colleague mia kivapelto me and i met uh more than 20 years ago at a alzheimer's meeting in stockholm and we've been working together on and off ever since and not relatively recently mia joined the board of governors of the alzheimer's drug discovery foundation um and she has also been the recipient of major international prizes including the goods prize which is the addf's annual prize to a leading internationally recognized physician scientist and drug developer and she's also received the ryman prize in sweden which is considered the nobel prize equivalent for geriatricians and i know most of us think about alzheimer's research and care from the neurology point of view but one of the things that me and i have in common is that we're both geriatricians and professors of geriatric medicine and i think it's safe for us to say that we take a different point of view than neurology in terms of the way we care for people but in terms of research as marx mentioned at our founding we when we incorporated our founding papers laid out that we would be involved in developing new drugs as treatments for alzheimer's number one developing biomarkers and blood tests that would accelerate the development of new drugs for alzheimer's disease and improve early diagnosis in the community and lastly prevention and i have to say that over the 25 years prevention is actually one of the hardest sciences to perform experiments on and to give a somewhat historical perspective on that we had a meeting an agdf advisory panel with one of our board members and several leading investigators about 2002 and at that time we laid out in a paper what was the evidence for risk factors for alzheimer's these things like exercise and diet and sleep and all of the things that were known at the time and we actually published the paper and we created a program called cognitive vitality which is on our website now cognitivevitality.org but all of that knowledge back 20 years ago was based on very not as strong data in other words it was based on associations it was based on sort of looking at populations over time and seeing what factors were associated with the prevention of alzheimer's disease now you can imagine that prevention takes 10 20 30 years so the question is what is the experimental paradigm that you could possibly use to prove that something that you did when your 40s ultimately leads you let's say to not have alzheimer's or delay the onset of alzheimer's when you're 75 or 80. you can imagine how hard and how expensive that would be and um what mia has done with your permission if i can say something is that she is really famous worldwide you're really looking at one of the most respected most acknowledged prevention science physician scientists in the world right now and i'll tell you two reasons why one is that mia came up with a model for actually doing the kind of experiment that i just mentioned uh the experiment that mia did which let her tell you much more about was to design a randomized clinical trial so when we look at evidence in science we think about levels of evidence and there's something called the pyramid of evidence and at the top of the pyramid the gold standard of evidence for any kind of therapeutic or any kind of science is called a in clinical is called a randomized clinical trial where you have a placebo group and you have an experimental group and you ask the question does your does your experimental group does your intervention does your drug work compared to the placebo and that had never been done in prevention science for alzheimer's disease and that's that was the concept that i think mia has really brought to the world and when i say the world her work that she's going to tell you about in the finger trial which stands for the she'll tell you what it stands for um that that her work is being replicated all over the world in every major country in the world in china throughout the european union in the united states and south america in 45 different countries is that right yeah that's great in 45 different countries the work that mia did in scandinavia where she's from sweden but worked in finland and now have appointments in london and karolinska and so on that work because every country wants to know you know what mia did in scandinavia is that true in the chinese population and they want to do it their way and their population to prove it so it's it's a really exciting what mia is doing is really really exciting now just before i close i just want to mention elaborated on a couple of things that mark mentioned um as you mentioned we've been i've been doing this almost 45 years and people would say gee howard you know you've been doing this 45 years and what do we got right i mean where's the cure but the fact is that as a physician scientist i think part of what we love is the process of science and we're all standing on the shoulders of people that went before us and we make incremental progress and we create new knowledge and we know ultimately that that's going to happen now i can tell you 45 years ago when i saw my first patient and opened the clinic for alzheimer's disease at rockefeller university in 1981 we didn't know anything about this disease and there's a historical reason for that which i don't have time to go into but alzheimer's is a relatively new disease i mean we had cancer research in 1900 velasquez opened a trust in the 1920s for cancer research when when we went to med school when i went to med school i never heard the word alzheimer's disease it wasn't defined yet when my mentor bob butler wrote a book called aging in america why survive he won the pulitzer prize for that book because he brought to the attention in 1975 of the coming epidemic of alzheimer's disease he predicted it he described it and he then went on to study to start the national institute on aging which has become the leading provider of research funds in alzheimer's in 1975. so we're late to the party in 1980 when i started we knew nothing so today it's amazing i mean it's just incredible what's what we have today our foundation started funding the first diagnostic test for alzheimer's in the year 2000 a brain scan that scan that work at penn was spun out into a venture capital backed a biotech company called avid radio pharmaceuticals in 2005 with seven million dollars in venture capital it was purchased by eli lilly and five years later in 2010 for 800 million dollars in milestone payments and in 2012 that test became the first diagnostic test approved by the fda for early diagnosis of alzheimer's disease whereas before the test you had to do an autopsy to define the diagnosis and not a lot of patients that i was seeing wanted to have an autopsy to make sure they had the right diagnosis as you can imagine but today i can write a prescription in my office they go down the block and get a pet scan and i can tell them with about 90 95 certainty that they have or have not alzheimer's and i know you're going to ask me what so why bother and we can talk about that and i'll give you i'm sure me and i can give you our answer but i'll just put it this way why don't alzheimer patients deserve a definitive diagnosis cancer patients do and they deserve a prognosis um so do alzheimer's now what's more amazing if you asked me five years ago would there ever be a blood test for alzheimer's i probably would have said no there's never been a blood test for any central nervous system disease any brain disease there's never been a reliable blood test on the market about two years ago a company that we invested in called c2n which was spun out of washington university came to market with a blood test for alzheimer's disease and that test is approved in 49 states now and on any given day i can actually write a prescription and just in terms of the normal process of care just like every other disease i can tell people with about 90 certainty whether they have alzheimer's through a blood test now these tests have revolutionized our work for two reasons it's revolutionized early diagnosis in the clinic and it's revolutionized the progress in clinical trials you've probably all heard about the controversy around the biogen drug right and the fact that this was an anti-amyloid drug that removed the amyloid from the brain and probably but not clearly was associated with a slowing in the rate of cognitive decline in patients that was one of the first trials that was ever done in 30 years of clinical trials and alzheimer's where entry criteria to get into the study was you had to have a positive brain scan it was the first time that 100 percent of the people in the study actually had alzheimer's imagine that when when we actually started doing these these brain scans on the people that were in the clinical trials it turned out that the neurologists and the other doctors who were enrolling people in the trials were wrong about the diagnosis about 35 percent of the time so how can you get a result when 35 percent of the people in your experimental group don't even have the disease that you're trying to test with a drug that's directed against this amyloid protein that we think is one of the causes of the disease they don't even have the amyloid protein in their brain and you're treating them with an anti-amyloid drug so this biogen study was one of the first not the only one there's about five or six others drugs like it and they use the test that we started developing at the university of pennsylvania in 2000 to be to make sure that everybody in the trial had amyloid in their brain they had alzheimer's disease and then used that test to show that the drug worked by showing that after about 18 months of treatment these people that had a brain full of amyloid and had alzheimer's their brains were cleared completely of amyloid which is amazing so that's that's really exciting we've learned how to do clinical trials and alzheimer's this is a huge um a huge amount of progress cancer had to learn how to do cancer trials we finally learned with biomarkers how to do and there's there are other biomarkers coming down the tight pike the company that i just told you about is is going to come up with another test on the market in the coming few short period of time which is even better test um i'm getting the plug here so i gotta end this but i'm excited i guess this is what i'm trying to say and um so uh i think i've covered most of what i wanted to mention um i could speak a lot about repurposing we've done a lot of repurposing and we have a hundred and the the field there's 120 drugs now in clinical trials around the world which is a lot for us and um for the first time about 75 of those drugs are not amyloid they're not tau they're not the traditional historical targets that have been used and they're following what we have been our strategy for 25 years at the foundation which is that aging is the leading risk factor for alzheimer's and as gerontologists as geriatricians we know something about aging and so we've been trying to translate what we know about the biology of aging into new therapeutics for alzheimer's disease and so we're looking at inflammation drugs we're looking at metabolic drugs we're repurposing diabetes drugs and guess what the leading diabetes drug in the world is metformin and everybody wants to be on it for some reason now but it it's it's an anti-aging drug it's not just a diabetes drug and we're very proud to be funding mia to add on to her lifestyle uh program which she's going to tell you about and i hope i'm not stealing your thunder here mia yes um is is um as we're ending that forum and if i may say it's my my last thing i'm going to say is if you think about heart disease how do we prevent heart disease you do lifestyle management you manage your diabetes and hypertension and you take a statin and that's the model that we're looking at in mia study that the atdf has funded and that she's conducting and with that i'm sorry if i went too long no this was exactly perfect thank you so let me turn it on to you thank you so much and thank you for the kind introduction and invitation it's absolutely my great great pleasure to be here and see you all and i'm very happy to talk about our research and the latest findings and i was thinking the title of this meeting hope on the horizon and there is hope on the horizon especially when it comes to prevention and i was thinking i will tell three things from our recent research which has been actually the basis for the finger trial which harvard mentioned and the three things are the following first i think the prevention is the best treatment we have today for alzheimer's disease we know that the process leading to alzheimer's disease may start to develop 20 or 30 years before we can do the diagnosis and that's why i normally say it's never too early to start to prevent dementia on the other hand it's never too late we have shown that in our studies that you can always do something for the brain health even if you would have alzheimer's disease the second thing is that there is a great prevention potential at least 40 percent for zero 40 percent of all dementias is linked to modifiable lifestyle related and environmental factors which could be prevented for me it's a big number and i say at least because the list of modifiable risk factors has been getting much longer during the last year when i started when we started it was only high eights and genes and now we have much more and we can talk much more about that later which are exactly the risk factors so this means that alzheimer's disease is complex is multi-factorial and for me it means that then if we really want to prevent it's not enough to only focus on one risk factor we need to focus on several risk factors and mechanisms at the same time the multi-domain intervention how we call it and that's what we have used in the female trial and the third con the concept which i like a lot is brain plasticity what do i mean with brain plasticity is that brain has a fantastic capacity to change and adapt and compensate even though there would be alzheimer chances so brain can compensate and everything what we are doing the lifestyle changes is affecting the function and the structure of the brain and that gives i would say the basis for the lifestyle interventions that we can do a lot for the prey so these principles we used when we started the finger trial more than 10 years ago actually 12 years ago and it was quite ambitious because there have been so many negative trials so people were a bit skeptical but can you really do this with the lifestyle chances and we did we we use the finger model we put together different modifiable risk factors so it's very easy to remember because it's like one hand and five things we have first a healthy balanced diet brain needs a lot of nutrients energy nutrients antioxidants anti-inflammatory nutrients as well second one is exercise physical activity we are i would say the heads down generation because we are sitting nowadays so much in front of the computers so every count every moment counts uh aerobic exercise but even muscle training and balance training because when we are getting older the muscles tend to we tend to lose the muscle mass so it's important to have the pro physical activity and the third finger what's that that's the cognitive training mental activities finding new challenges learning new things in the same way we are training our muscles we should train our brain fourth one is social activities and i can think that i mean the pandemic has been showing us how important the social activity social interaction and social engagement so that's really important for our brain function and the fifth finger that's taking care of all vascular risk factors high blood pressure high cholesterol obesity and diabetes what is good for the heart is good for the brain and that can be done with lifestyle or with drug treatments with this package we could saw that the memory was 40 percent better uh executive function how we are planning different things and how we are doing multitasking 83 percent more more improvement and even processing speed how quickly we can do different things 150 percent more important we could also see better functional level better quality of life and risk of other diseases went down with 60 percent and the good news were that the persons who had the genetic risk april even 4 got a clear benefit so we can't change our genes but we can try to reduce the genetic influence so as you mentioned howard this finger model is now tested and adopted globally 45 countries it has been really really wonderful and i'm sure we will learn a lot from the worldwide fingers and we also get the big data with which we can learn either and the next step finally what we do now is to upgrade finger to finger 2.0 so that we can combine the lifestyle intervention with a possible disease modifying track and because of the reasons mentioned there is a lot of links between diabetes and alzheimer's we have been selecting a drug method some researchers are really saying that alzheimer's is a type 3 diabetes because there are so many links between diabetes and alzheimer's disease and i'm very grateful for the support from addf that we can start the med finger trial for me it's really the next generation of clinical trials where we combine it's not lifestyle or drugs but we can see the combination so i'm very optimistic for the future there is a lot to do still left a lot of research but i like when the hope is linked to action and now we are doing the randomized trials is the highest level of evidence and we can implement the results immediately so here all hands and fingers are really needed and thank you all for your support thank you well we i'm sure there's a lot of questions about prevention we always get a lot of questions and i just want to just raise your hand and i'm happy to you know we'll recognize you and happy to answer any of your questions i'd like to start there's a genetic risk factor for alzheimer's disease called apoe and while about 20 percent of the population has this genetic risk factor which apoe is a protein in the blood that carries cholesterol and does a whole lot of other things in including in the brain but 60 of people with alzheimer's disease have an apoe4 uh gene so there's three genotypes apoe 2 apoe3 apoe4 and as mark mentioned actually we're funding a biotech company called lexia that's trying to um genetic give genetic therapy to change the genetic apoe4 risk factor which increases if you have two of those genes one from mom one from dad you have about 20 15 to 20 times the risk of getting alzheimer's disease we've known about this almost 30 years but we haven't been able to figure out a drug and we think that we figured out a druggable way to fix apoe4 by giving people apoe2 which is protective through gene therapy into the brain and as mark mentioned we just got first results from the company that was spun out of uh out of while cornell in new york um to do this um and so in clinical trials people with apoe4 react very differently than people who have 8.3 which is the most common type in the population so i asked mia if apoe4 if the people with apoe4 gene uh had any different response to the lifestyle and to finger and they did that was the positive new in the finger trial that apoe4 carriers got the clear beneficial effect of the intervention they got more effect than the apoe for non-carriers so i think that's a great great news we can't change the genes but if you have the a4 you could really really great effect so i think especially if you have the family history or if you have 804 the life study interventions are important and for me that raises two questions actually i mean one is um why do you think gabo e4 is doing that do we have any idea it sort of illustrates that we can create these findings but we don't really understand how they work and that's kind of our job that's what we're interested in is if we can understand how these relationships between let's say april e4 and an improved response to prevention worked then maybe we would help us to figure out the drugs um how do you think apoe4 might work to give a better response to your lifestyle interventions i think we don't know yet all the answers but what we know is that apoe4 carriers seem to be more sensitive or vulnerable for harmful lifestyle factors it can be smoking it can be alcohol physical inactivity or different things we have been showing it in epidemiological studies and experimental studies and now i said for the first time we could so in the finger trial that we can do the opposite if you have apoe4 you can reduce your risk with healthy lifestyle so for me it's really optimistic finding you can try to in a way reduce the negative impact your genes are having and we see the same effect for other genes as well there is a lot of focus now on polygenic risk score for alzheimer's disease and we saw exactly the same effect so what is my kind of vision is maybe we can't always totally prevent alzheimer's but if we could postpone the onset with five years with 10 years with 15 years the same we are doing now with cardiovascular diseases so that's and when we combine the drug there then we can get it maybe even more effective when patients come into my practice and i'm sure yours um and they have a family history like you mentioned like a sibling or a parent that had alzheimer's and particularly if you have 8.4 then people tend to get it 10 years earlier so instead of 75 they might be getting it at 65 and so or somebody's healthy let's say they're 55 or 50 and they're probably pretty healthy they don't maybe they have a little bit of memory problems and they they tell me that their father had alzheimer's disease and when i see those people i do their apoe4 testing but most doctors are very nihilistic about that and most patients will say well why should i bother knowing my genetic risk factor is you know and i'm wondering for two things what you tell your patients but also um what now that you have these results about lifestyle impacting able before people if that gives us more power to tell people get the apoe4 and if you got the april 4 you know you better stick with the regimen yeah that's a good question we i mean we could say that lifestyle healthy lifestyle is good for all but of course if you know that you have the family history or 8.4 especially then you should do that and we do it at our memory clinic for all not all persons want to know it but we disclose the genetic for those persons who want that it can be a motivational factor that when you know that you have an increased risk and you can do something for that i think for the future if we could so that some drugs are having more effect if you have 8.4 or not then the importance is even greater and that's something we do in the mid finger trial because we want to have at least 50 percent of the participants having 8.4 and then we can see if the effect is the same if you have 8.4 or not so after some years maybe i have new results concerning that any any questions yes in the united states uh quest and lab corp offer it so your doctor should be able to um figure out the code for that test and it's just a regular blood draw and they do the genetic testing at the um at the labs and it's you know so it's national it's all over the place and it's i don't know if your insurance will pay for it but it's it's readily available yeah the quest test is called cardiac cardio cardio iq or at least it used to be and it's a it's a very typical test bonnie howard um thank you both doctors um so if you have two or three how many people with two get alzheimer's so about five percent of the population has an apoe2 so it's not common and their their risk relative to the standard which is apoe3 is reduced i forget how much it's reduced but but it's reduced it's a protective it's a protective gene but yes and three seventy percent of the population has apoe3 yes so what percentage of apoe3 people get alzheimer's that's a great question so um the only thing i can really say in that regard is that i guess about at age 75 about 25 percent of people will have alzheimer's disease and then if you figure out that sixty percent of the people with alzheimer's disease have a well before you could do the arithmetic and i could give you an answer to that but what happened because i have four months [Music] oh well and yes and what you said howard was also that the high aids is still the most important risk factor so after the 65 years of age the risk of alzheimer's doubling after after for every five years it goes really up after 65 after 75 after 85 and if you have one april e4 your risk is two or three times higher maybe three if you have two it can be up to ten times higher and you get the disease earlier so do most people get two results when they take the blood test you get one result and it's it's all in the same piece of paper it'll say like you're three four four four two four i thought you got actually two you got two results you you have every every person has two genes two what we call alleles right of a gene um you one from your mom one from your dad okay and the report is but the report is all in one piece of paper okay but they give you two two different right yeah you get two numbers okay so just out of curiosity a long time ago i did 23 of me but it wasn't a blood test i mean this is a while ago i think you you did a saliva and you had to send it away and this thing i don't know is that still are they still using that or is a blood test better than what they were doing i would say the blood test is probably better and it's um but it depends on who's doing the test and how it's done right okay thank you uh yes sir yes absolutely i'll let me take that one um i think we could warrant further discussion the question is is diabetes how strong a risk factor how is diabetes a risk factor type 1 type 2 diabetes for alzheimer's disease or even for vascular dimension even cognitive decline with aging so we sort of have three things we're kind of talking about today one is how we age and get cognitive decline one is alzheimer's and the other is other forms of dementia but i'll let mia talk about diabetes and i can start so diabetes is one of the established risk factors for demand support alzheimer's and vascular dementia it's type 1 type 2 diabetes both there have been more studies with type 2 diabetes because it's more common and you often have it later in the life even pre-diabetes even before you get the diabetes diagnosis is increasing the risk meaning that you have slightly elevated glucose levels so so it is an it is an important risk factor and what are the mechanisms i think is important we don't know all yet but i think is as i mentioned some researchers are saying that alzheimer's is the type 3 diabetes because it's so closely linked mechanistically with diabetes there are for example links between insulin insulin resistance and pita amyloid in the brain so it's very closely linked with these real alzheimer mechanisms another mechanism is inflammation there is more inflammatory response in diabetes and that's also linked with alzheimer's disease and then as mentioned a lot of vascular mechanisms the endothelial function in the blood vessels the blood flow to the brain is getting uh impaired and quite many all the patients are not having pure alzheimer's disease it can be the mixed demands it can be both alzheimer's and vascular so in that way if i'm thinking prevention metabolic syndrome and diabetes is really one of the important risk factors and that's why we wanted to take the metformin as an add-on to the finger packets there is something good um the brain is three percent of the body weight right um but it uses 20 of energy that comes from glucose at any given moment it's the highest metabolic organ in our bodies and it gets most of its energy from glucose okay so when you're thinking you're using glucose and that's why we can actually look at how people think now with functional mri and pet scans and we use pet scans that measure to use a form of glucose that can been seen on a pet scan to look at brain function if you think about it what's the first thing that happens when a diabetic becomes hypoglycemic and their blood sugar drops below let's say 60 or 55. the first thing that happens immediately they go unconscious and then you give them you know some some sugar on their mouth and they wake up like that that's how sensitive the brain is to glucose now if you're a diabetic and you have insulin resistance and your brain on a chronic basis can't use glucose efficiently that's going to lead to neurodegeneration and then in a simple way that that's an example of how diabetes is is a risk factor i would say um okay mia so uh hoover paiva tervetuloa we're happy to have you here from finland can you give us any of the data is there any big data on metformin and how effective it is that's a good question so the evidence concerning metformin and demensa and alzheimer's disease comes mainly from epidemiological studies observational studies showing that people who have been using metformin have a lower risk of getting alzheimer's even compared to other diabetes medications so that's quite strong thing now that we can see it then there are a lot of experimental studies showing these links between diabetes and demands there are some randomized control trials actually funded by addf showing among patients with mild cognitive impairment that metformin improved memory and some other cognitive functions and there are now larger trials on going to see really if this effect is there the combination lifestyle and metformin has never been tested to prevent dementia and alzheimer's and that's why we have the meth finger trial because we don't know yet what is the best dose is it 500 is it 1000 is it 2000 are there some side effects when to start it so all these questions i hope we can answer at least partly after the mid-finger trial but it's a safe drug is is generic it's well available it can pass the blood pressure barrier and that was the reason why we started it and why many people are actually using it already today and there are other diabetes drugs being tested like we tested as mia mentioned we already funded a study at columbia university several years ago of metformin for alzheimer's disease and saw some really interesting results and we tested a drug at the imperial college of london called lyric glutid which works by a different mechanism but is also an anti-diabetic drug and now that that trial was fairly positive and novo nordisk is testing the next generation of that kind of what's called glp with one agonist a drug called semi-glutid that you see on the nightly news every night it's called rubelsus and they have a jingle and everything but that drug is also being tested for alzheimer's and in that class every single drug that's been tested has shown positive results so there's something to this improving energy utilization in the brain and how sensitive the brain is that you know i think we're on to something at einstein uh medical school there they have a longevity team and study and one of the outputs of that i believe is they've defined some longevity genes correct could you tell us a little bit about the inner relationship of those genes with the genes that you've been referring to yeah so let me say you're absolutely right neil you're near barzillai and albert einstein is doing a study called i'm in that study it's called the tame study and study that is actually looking at um aging as an indication for the fda because up until now the fda could not recognize aging itself as a therapeutic indication if a drug was approved for aging then everybody would want to go on it and they couldn't figure out you know how to measure it how to measure and i think what near has really brought to the field is convincing the fda that there are ways looking at how many chronic diseases a person gets and so on to look at outcome measures that would be if that would be fda approvable and he's using metformin in that study as an anti-aging drug not as an anti-diabetic um and he's going along you know and this reminds me about one thing in the finger trial we could also saw that the finger intervention was uh counteracting the shortening of the telomeres and telomeres is one marker of cellular aging the telomeres which are in the chromosomes like the cap kind of protecting them so for me this is again an indication that if we are thinking mechanisms there are probably a lot of aging related mechanisms also behind things so would you say the aging genes operate independently of the alzheimer genes or is there an inner relationship no i would say they probably we don't know so i mean the the real answer is we don't know but um i think while aging is a risk factor and these mechanisms play a role in the aging brain at the same time alzheimer's is a disease of old age and there are certain things that probably um are different from aging itself or related in some way to as you say the longevity drains but i don't i don't know of any longevity we funded a centenarian study a number of years ago blocking on the guy's name at harvard and he looked at how many people at the age of 100 had dementia and it was only about 40 percent so that means 60 percent of people could make it to a hundred and really have intact cognitive function and he wondered if it was a gene because if if somebody makes it to a hundred it's really unusual and he had these families seven hundred families around the world where he looked you could he had a picture of the family i'll never forget and there were i think seven generations in the picture there was the 110 year old matriarch with the 90 year old daughter with the 70 year old granddaughter with the 50 year old you know great grand whatever and and the chances he used to say the chances of this happening where not only that but everybody if like a man lived to be a hundred and there were five siblings all the siblings lived to be a hundred and what he would say is that this is genetic this kind of extreme longevity is genetic and he wanted to find out what the gene was and he found a law he found a gene and he started a biotech company to to create a drug based on the gene and in the end that failed and i think the point my point is that these genes are really really interesting as i said before we've known about apoe4 it's it's such a robust risk factor for alzheimer's for almost 30 years and i think this last week we had maybe some of the first encouraging draw results that maybe we're on to something to try to fix that gene um it's really hard just getting a gene and then getting a drug it's it's really hard it's a long way yes yeah so the question is it's a good question um for people that want to get metformin who aren't diabetic would your physician be willing to prescribe it and um i get that a lot to be honest um and i think that this is what we call repurposing so our foundation has a big program in repurposed in the last two or three years we've gotten results from about 10 different repurposed drugs anti-hypertensive anti-diabetics cancer agents and on and on and on parkinson's disease agents and and prescribing them off label now i prescribe off label i have some confidence because i i know the trials i know the results and i'm willing to take the risk i could be sued for prescribing off label but also the drug comp not the drug companies the insurers don't want to pay for off-label use especially especially if drugs are are expensive so there's a we're having a whole discussion at the foundation about next steps how are we going to create an indication for a repurposed drug and the example of a repurposed drug is the little mind one of the classic examples i'm going a little bit off here but but just to give you an idea of the question you're asking thalidomide was a terrible drug in the 50s for pregnant women but then somebody realized it could be an anti-inflammatory it could be used for myeloma a company called celgene which became the most successful biotech company in the history of of the world actually repurposed the linomide for myeloma and that drug is still on the market for myeloma today so you're asking me would doctors prescribe metformin off label for someone who is not diabetic and i've seen a lot of resistance to that and one way that i try to manage it is by doing the hemoglobin a1c and if somebody's kind of pre-diabetic then i'll certainly start them and if they're almost pre-diabetic i'll feel a little bit more is that what you do diabetes having metabolic syndrome this kind of thing so it's used in europe at least increasingly there so yeah i i would say that the indication is getting more to that direction since the um insulin resistance i'm right here sorry insulin resistance has a high degree of correlation um with your study uh there's been a fair amount of informal uh work done on on diet exercise and so forth have you incorporated that along with the with the drug studies and been able to isolate it from from the drug so that particularly as it relates to insulin resistance there's been some very good results with plant-based diets and fasting and so on so if i'm thinking what is the effect of the eats of the fingers or diet the physical activity or the drugs or in the finger trial we only had lifestyle that was only lifestyle based and it's quite difficult to separate totally what is the effect of physical activity or diet because they all are interacted of course with each other we are just now analyzing all the biomarkers which we have been collecting the finger trial was for two years and now we are ready with the 11 year follow-up and we have been collecting the biomarkers all the time so we will learn a lot about the underlying mechanisms results so far are showing that there is happening something with insulin resistance yes only with lifestyle with inflammation with oxidative stress so the mechanism seems to be quite multi-factorial as well a lot of things are happening what we will do in the mid finger trial when we add the drug not for all but for a part of the study population then we can surely see even better how big additional effect is is coming when you add the truck so that is my hope that after the trial we can more separate the effects yes sir good i i have two two questions the first is that actually i've been having discussions with science with a scientist and engineer about nitric oxide which was used and is now really out of the patent stage so there's research done which can actually destroy a lot of the plaque that's been built up and they've done this in premature children i'm wondering if you have some insight into that the second is it relates to this uh real result this new you know drug that's in second stage about i'd like to have your comments on that those two sure um so we've funded um drug programs around nitrous not there's different forms of nitrous oxide so i won't get in but there there was a company called adonis based out of san francisco led by a guy named stuart lipton um and he had created a molecule that one of the drugs on the market is called mementine and he had created a molecule that was the nitro mementine on the same theory that you're talking about to bring to bring nitric oxide into the bloodstream because it you you know you can inhale it and it's happy gas but we're not going to do that to 85 year olds and as a treatment for alzheimer's disease so we needed a druggable way to bring nitric oxide to into the bloodstream so the way he did it was by putting that no nitric oxide onto an existing drug and and then taking that combination and it didn't work and they dropped it i think it's it it it's a it's an idea that's out there for various reasons including the effects of nitric oxide on the on the endothelium on the on the blood vessels and so on but it hasn't been druggable you asked about williamson and i have to say that we did a we funded a clinical trial really is always a parkinson's an als truck and it's one of the old maybe one of two als drugs that have ever been shown to slow the course of als and as we most of us know this is a horrible disease people are dead within two years or so at their diagnosis it's a progressive neurodegenerative disease and being able to treat it is remarkable really is all works through a neurochemical system in the brain one of the most prevalent called the glutamate system and when there's too much glutamate in the brain there's something called glutamate neurotoxicity when you have too much glutamate at the synapse it kills nerve cells this is a well-established mechanism and the way there's a the same drug that i just mentioned actually mementine works somewhat through this glutamate system although the mechanism of action and its effect on cognition isn't necessarily thought to be that way really is all is a very effective glutamate modulator at the synapse so we funded a clinical trial at the rockefeller university in mount sinai in new york and that was published about about six months ago and it was it was quite an interesting study with a lot of positive results it was a phase 2a exploratory study we're looking at funding a follow-on trial now and various other things in terms of creating a way for us to help the commercialization of really solve for alzheimer's disease but what i'm really excited about and i've never said this before publicly privately or thought it is that i started prescribing really is all off label in my practice and in 45 years of practice i've never had anyone and please don't take this as hyperbole i mean this sincerely i've never had anyone come into my office and say that drug is amazing or that we were stunned when we started that drug and i'm not sure what it means i i don't want to you know create expectations that don't exist but a lot of times we learn from our patients and we need to listen to what our patients are telling us and a lot of times anecdotal responses are useful so i think your question about really is all i'm actually quite excited about that drug and the foundation is trying to figure out a way to pursue it yes larry on a per capita basis is the epidemic growing uh over the over the last 20 30 years so so question one i was you know did this exist 2000 years ago and and you know cicero and i'm not an expert like i'm not very literate to be honest but um but but uh you know i know cicero and marcus aurelius talked about senility in old age so this has been around forever you know there were people in in the greek and roman times that lived to be 80 85 and ended up being senile and i forgot your other question oh is the prevalence increasing okay so um the you know the the um aging is the leading risk factor societies are aging all over the world developing societies and undeveloped societies are aging even more rapidly than the developed world so as we go forward alzheimer's is going to be a greater problem for countries like india than it is for you know the united states and europe and the number of cases is growing but interestingly there's a difference between prevalence in this incident so prevalence is a scientific term describing how many people actually have the disease in a year an incidence is how many new people get the disease in any given year and there was a study in the united states from the what's called the framingham study which is a very famous longitudinal study that showed recently that while the prevalence of alzheimer's is going up there's more cases because there are more people getting old the incidence of new cases is going down and it's the first time that we've ever seen that probably because of healthy lifestyles that we're actually having an impact and we're starting to see it yeah and this is exactly what was thinking and the same findings have been not only in u.s but in sweden in europe in many other european countries so the numbers are not increasing as much as we could if i'm thinking the numbers globally we can really talk about demands epidemic every three seconds someone in the world is developing dementia 50 million cases today 2050 the number is 150 million and as you said our largest increase in low middle-income countries and i said that the the incidence has not been increasing as much in western countries but in asia it seems to go up so there is something going on with the lifestyle and again it's a positive thing because that's maybe something we can do something about yes someone recently told me there may be a link to dementia and taking a statin and i wonder if there's any truth to that so about 15 years ago we funded a study that nobody the question is what about statins basically right so we were very interested in statins and as mia mentioned high cholesterol is probably a risk factor for alzheimer's disease and certainly for dementia and literally like 15 years ago we were very interested in stem so we went to the different drug companies to see if we could get a partnership and they all said no because they had a great franchise for cardiovascular disease and basically we think that they didn't want to take their franchise by doing a study and all people maybe they'd get side effects or whatever so we gave an investigator in phoenix 750 000 dollars to start a small statin trial for alzheimer's and we worked with him for a long time to try to figure out which statin to give do you give statins that get into the brain or do you want to give statins that don't get into the brain and we ended up choosing lipitor it does get in the brain and then we went to pfizer and we said this trial is going to go on whether you like it or not you want to be involved and they put in about seven or eight million dollars and we ran a trial of almost 3 000 people at the time and actually it turned out the trial of lipitor didn't work but there's a lot of thought now that the trials that we ran 15 20 years ago just weren't done right and if if anything i would say that you know we probably need to run those trials again the evidence that statins probably reduced the risk of alzheimer's i personally think is very strongly i don't know what your thoughts are you have the evidence from epidemiological studies that people using statins may have a lower risk but we do not have evidence from randomized trials and that has been methodologically quite difficult to get that evidence one more tricky thing with the cholesterol is that cholesterol is not passing the blood pressure so there is like a little bit the crosstalk and we have been working a lot with oxysterols that are kind of metapolites and we have some evidence that if we lower the cholesterol in the blood something is happening in the brain as well so i believe there is something with treating cholesterol when needed with statins so we of course need still more studies but that's my clinical experience but but it's also true that cardiovascular disease and stroke are risk factors for dementia so by taking a statin you reduce your risk of cardiovascular disease arrhythmias low profusion stroke and you know stroke is a risk factor for what we call vascular dementia which is the second most common cause of dementia and as mia said before most people in the community don't just have pure alzheimer's disease they have alzheimer's with tiny little strokes that we see on mri for example and and there's a lot of momentum now there hasn't been much work in vascular dementia but there's a lot of interest in vascular dimension now and hypertension which we haven't talked about at all yes hypogenic so there we have actually randomized control trials the sprint mind trial showing that if you really lower the blood pressure you can reduce the risk of mild cognitive impairment and demands that i think was a wonderful trial because again it has been more difficult to solve the effects in a randomized trial but here we have both epidemiological and trial evidence we haven't talked about hypertension but it's an even more power i would say it's an even more powerful risk factor for dementia both alzheimer's and vascular than diabetes and if you have high blood pressure manage it because then bring it down as low as you can tolerate because it's it's been shown that hypertension is sorry no i was yes yes because i was just thinking also the list of other risk factors that blood pressure indeed is one of the very important ones and i mentioned the list of modifiable risk factors there are also new factors which we have not even talked about that maybe we have no time today but i was thinking like stress sleep hearing loss air pollution so the list of modifiable risk factors is getting longer and longer and again there are different types of treatments or management for all of this like hearing loss is quite common and something we can do again we both are geriatricians so again the holistic care is really something when we think both the prevention and treatment i think we have time for one more question and then we have to and that's sir so i commend both of you for working on an intractable problem uh but my question is in talking to a lot of friends of mine that really get involved in in financing medical research there really hasn't been the enormous amount of money put into alzheimer's because since 1992 or somewhere way back there hasn't really been anything successful in terms of a drug and the second question is why would we want to have a test that says that we're prone to it when there really is no cure for it isn't it better or is it not better that we just lead our life because we really can't do anything about it i mean so well and these are especially for everybody in this room these are scary thoughts to have to deal with yeah well in answer to your first question that's why we're here tonight that's why the alzheimer's drug discovery foundation exists because investors are afraid and they're primarily interested in making a profit and we're primarily interested in finding effective treatments that are safe and that's why we've invested almost 200 million dollars over the last 25 years in almost 700 drug discovery and development programs in 19 countries nih the the uh the the government has uh gone from spending 500 million dollars a year on alzheimer's research to a budget now about 3.5 billion they become the third largest institute in at the nih and the drug companies are coming back now because now we have those biomarkers and the biomarkers dramatically reduce the costs and the risks of developing drugs for alzheimer's and the science has come of age so i agree with you uh industry and investors have been uh reluctant the risks have been great but i think you're going to see a big swing and an answer to the second question there's a concept in health economics called willing a willingness to know wanting to know and that applies in medical practice and as well i could tell you you have cancer and you could say to me well why do i want to know you know why i don't want treatment i'm 80 years old i don't want to get a psa test i don't want to have an x-ray even though i'm coughing up blood i don't want to know and so it's what we call in medicine shared decision making some of my patients want to know they want to get the brain scan they're going to get the blood test they want to find out if they're able e4 positive and then they want to go out and do everything they can leading healthy lifestyles and maybe contributing to medical research and some people don't want to know but the fact is that now we have technology out there that can help people who want to know find out participate in clinical trials i mean this blood test the cohort of people out in the community that are firmly diagnosed with alzheimer's is very small and one of the biggest expenses one phase three clinical trial cost 400 million dollars in alzheimer's disease and we're trying to find the patients for that trial is 50 percent of the cost of that study by going from requiring brain imaging at eight thousand dollars ten thousand dollars an exam to a blood test that cost a thousand dollars an exam is going to dramatically reduce the cost and improve the efficiency of how we do clinical trials and because it's going to create this cohort of people that are diagnosed and they're going to get it early i'll say one more thing to close mia mentioned about prevention the technology that we have now can identify people in their 40s and 50s who are beginning to get alzheimer's and won't have their first symptoms until 20 30 years later and there are clinical trials going on now that are looking using these biomarkers these blood tests and these brain scans to find people who are suffering this disease but don't have symptoms and it's estimated that there are 47 million people in the united states that have alzheimer's disease and only 6 million of them have symptoms okay it's like most of the men in this audience have heart disease very few of them have had um have had a heart attack but everyone's getting the cholesterol and they're all going on statins and if they've got an 80 occlusion they're going to get a stent before they get the first heart attack um this is the world that we've created this is the new world and it's in so the biomarkers have enabled prevention uh and there's a study now of this same drug that was just controversially approved by the fda and the others that are like it anti-amyloid drugs where people are being screened they're asymptomatic they have amyloid in their brain and they're going on treatment to see if they can prevent primary prevention called that or whatever to see if we can prevent them from ever getting symptoms so the answer to your question is it's going to it's a new world it's an evolving world but the most important concept when we're talking about the individual is the willingness the wanting to know and then can we do something about it i think for my patients if they know that they are cooking alzheimer's they they want to do something about it and we can help them um if i could just ask people if i could just ask people just keep your seats for one second and if i could just have your attention because i have two public service announcements to make a big thank you i want to do for a couple for a few people in this room including these two people behind me and maybe an editorial at the end the two public service announcements i only know this because i was texted the second one just recently and i realized i had a first one text to me that said please tell everybody to turn off their cell phones before you start the program mark missed that one but i did read the other one for folks um for some of you who got here early there was a slight glitch at the table assignments and we can just ask we have three people stationed at the back just like kind of at a wedding as you leave just double check your table number again it might affect two or three of you but we'd rather you all be sure as you go out thank yous thank you i want to start with i want to stay right there don't go anywhere i want to start with tom and heidi mcwilliams who part of our board at the addf and we've really brought this science seminar series this is the third in a series tonight there's going to be one more that we're going to do in april that you've brought this to us thank you so much heidi also happens to be a co-chair this evening with the incomparable nancy goods and her wonderful goods prize as well as none other than her own bonnie lautenberg here tonight so and i know many of you were friends thereof so we have fabulous co-chairs you'll be hearing more about them tonight thank you let's say i pinch myself and i'm sincere about this howard one of the top alzheimer's scientists in the world mia the top prevention alzheimer's scientist in the world and we are with them tonight and that is pretty fantastic and how fabulous were they cute and just one last thing because i do think that last question was the perfect to end on and i want to share a story because i have the privilege along with howard to meeting with bill gates to meeting with jeff bezos to meeting with mackenzie scott and why they found the addf to become involved with us bill gates fathers passed a little over a year ago knew his father had alzheimer's he went to the capital markets he went to big pharma heard a lot about the amyloid theory and through his own diligence thought there's another way we're missing something here and when howard passionately answered that that that's what the foundation thank you to the lord her family has been doing for a quarter century was to get out to this moment the addf funds more diverse clinical trials than any entity in the world little old addf punching above its weight the last piece i'll tell you jeff bezos and this is direct from jeff bezos and it's no offense to the capital markets no offense to pharma but he said that it's not an efficient way to get a drug to market and he said don't take it too great but i just looked around and i saw the venture philanthropy model the prevention combined therapies precision medicine approach the biology of aging that howard talks about it and he said i'm giving my money to the addf okay so i'm not the brightest person in the world they're two of the brightest people in the world they found us just like you all have tonight so thank you

Channel: Alzheimer's Drug Discovery Foundation

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Id: LRecJSqhL24

Length: 70min 45sec (4245 seconds)

Published: Thu Mar 10 2022