Max Lugavere on Controversial Alzheimer's Drugs and Studies

Especially in the field of Alzheimer's disease, there was this huge revelation recently that the past 16 years of Alzheimer's research in many ways was built on fraud. Yeah, I read that. That is one of the things that I wanted to talk to you about because it's so crazy. Please tell people about this because it's so insane and it's so hard to believe that this could happen in modern medicine, especially with something that affects so many people as Alzheimer's. But please tell people about this study. Yeah, so basically the prevailing hypothesis as to what causes Alzheimer's disease over the past century has been what's called the amyloid hypothesis. So ever since Alois Alzheimer discovered or named Alzheimer's disease in 1906 and looked into the brain of the cadaver and saw these plaques aggregating around neurons, in the extracellular space around neurons, the plaques have come to be the focus of Alzheimer's research really. The idea was that these plaques were the causative force in the condition. Much like the plaque on your teeth, you see these plaques in the brain of a person with Alzheimer's disease. That's really been the target of drug therapy. The idea was that until we can find a drug that would reduce the plaque burden, reduce the plaque, get rid of the plaque in the brains of a senior person, somebody who's at risk for developing Alzheimer's disease, that it's a disease that you can't prevent, there's nothing to do to treat. But the problem was that they can never actually tie the plaque to cognitive decline. The clinically meaningful symptom, the symptomology of Alzheimer's disease, that it messes up your cognition, that it makes you forget your loved ones, ultimately forget who you are, ultimately forgetting how to eat and nourish yourself. They could never tie those symptoms to the plaque until a paper published in the journal Nature in 2006. What happened was this researcher named Sylvain Lesney at the University of Minnesota basically was looking into the brains of mice who are bred to overexpress what's called amyloid precursor protein, which is the precursor to amyloid beta, which is the protein that makes up the skeleton of these plaques that we see aggregate. What he did was he isolated a subtype that he called A-beta star 56 and injected it into a young and healthy mouse, or rat, mouse. He saw that that mouse's cognition rapidly declined. That was the missing link, that he found a subtype of this amyloid beta protein that serves as the backbone of these plaques, which could never be pinned to the cognitive decline itself, the memory loss itself. But he claimed that he found it, and when injected into the body of a healthy mouse, he saw a rapid decline in terms of their cognition. That was the missing link. At that point, faith in the so-called amyloid hypothesis was starting to wane because they couldn't find effective drugs. Alzheimer's drug trials have a 99.6% fail rate, so worse than for cancer, worse than for any other disease state really. The drugs that are currently FDA approved on the market, they're biochemical band-aids. They're minimally effective. They modulate various neurotransmitters, but I've heard it described expecting to remove amyloid from the brain of a person with Alzheimer's disease, and to see their cognition come back is sort of like thinking that if you remove all the headstones from a grave, people will come back to life. There's widespread neuronal dysfunction and death in the brain of somebody with Alzheimer's disease. In tandem with that, scanning technology has allowed us to look into the brains of healthy controls. What we see is that there's amyloid plaque in the brains of healthy controls as well. There's no correlation between amyloid burden in the brain and one's cognitive abilities. But nonetheless, when this paper came out in 2006, it renewed fervor in terms of this hypothesis because he found the subtype of amyloid that could be injected into a young and healthy mouse that would then seriously impair their cognition. That renewed interest in this hypothesis, and it's what ultimately led to the fact that just a couple of years ago, two years ago, there was a highly controversial drug that was approved by the FDA called adjucanumab, or adjuhelm. This is a drug that effectively reduced plaque burden in the brain for the first time they found a drug that could actually reduce plaque burden in the brain, but it didn't lead to any improvement in cognitive symptoms. I guess it was given the green light against tons of opposition that the FDA received. They put together a panel of 11 people, neuroscientists and neurologists, right? Eight of them told the FDA not to approve this drug. What was the reason for that? The reason for that was that the drug didn't move the needle on any clinically meaningful symptom. Were there significant side effects for the drug? There were. 35% of the people in the trial had significant brain swelling, and half of them had bleeding associated with that brain swelling, because these are antibodies. Adjuconumab is an antibody that basically causes your own immune system to target the amyloid plaques. What that's doing is causing an inflammatory response in the brain. 35% of the patients in the phase two trials, I believe, had horrible side effects and no clinically meaningful effect on their cognition. But nonetheless, because it effectively did reduce the amyloid plaque burden, there was this intense pressure to get it green lit, because that's like the amyloid hypothesis right there, right? Huge problem. One of the big vocal skeptics about this drug, Adjuconumab, is a guy, a Vanderbilt researcher named Matthew Schrag. Matthew Schrag was very vocally against the approval of this drug, which again, doesn't do anything. Horrible risk of side effects, no clinically meaningful effect on the symptoms that we want to improve for a patient with Alzheimer's disease. He was vocally critical of that, and then he also was working on some other drug. What was revealed basically in the science paper that came out was that he was dabbling on a website called PubPeer, which is a site where you can go. It's known for post-publication peer review. Before paper gets accepted for publication, it undergoes this peer review process. He found that there were a lot of red flags that were being brought up on this message board essentially about this nature paper, this seminal nature paper that was published that was the missing link between the amyloid hypothesis and the clinically meaningful symptoms, meaning memory loss. He did a bit of image sleuthing, which is not generally part of the peer review process. He looked at the way data is illustrated in this paper as it is in research. Generally, it's called a Western blot, which is a visual representation of data, the presence of proteins and so forth. He found that they were all, for the most part, fabricated. In fact, this A beta star 56 wasn't found by any other team, hasn't been found by any other team. It basically came to light that it was essentially fake. The whole thing was faked. What was the motivation for this person to fake all this? I think that we like to believe that science is this good faith endeavor towards human flourishing. In the industry of science, there are flawed humans, just like there are in every other industry. Scientists in general, I see this all the time in nutrition online on social media. Social media is a great ... They say that sunlight is the best disinfectant. Social media is a great way to see how this plays out because scientists are notoriously territorial, obstinate. Their reputation's egotistical. Their reputations are everything. I see it every day. They're humans. Yeah, exactly. There's bad apples. I think a lot of people in science ... I live and breathe nutrition. It's the thing that I'm most passionate about in life. Fitness, nutrition, sleep, disease prevention. My mom is what galvanized that passion for me. My mom went through it. My desire to prevent it from happening to others that I care about, and ultimately people from all walks of life. But a lot of people go into science, go into medicine because it's a career path. It's a career path for somebody wanting validation. It comes with prestige. It comes with money. It comes with all the things that make sense that a person would want, but then ego gets in the way and it becomes really problematic. You see it in nutrition all the time. You see it in nutrition all the freaking time. This person that fabricated this study and fabricated all this data, what consequences are there for that person? I think that the Department of Justice is going to be looking into it. I'm going to be looking into it. If they're not already, yeah. If they're not already. But I personally ... One of the worst things about this is it's not just the lost time and all the money that went to continue looking down this path of the amyloid hypothesis. Something in the wrong place, really. Because amyloid is there, but it's sort of like what you see in atherosclerosis, right? Like, cholesterol. It's like everybody has pointed at cholesterol as being the bad guy because cholesterol is clearly there in atherosclerotic plaques, right? But what's causing it to be there? That's the question that these researchers should have been asking all along. Some have, right? There have been other ... My mentor, as I mentioned at Cornell, who I've been lucky enough to work with over the years on certain projects, knew that there was another way. It's this glucocybometabolism, right? But there's no money in that. There's no money in saying, keep yourself as insulin sensitive as possible. Reduce your exposure to environmental pollutants. Don't hit your head too hard. All these different modifiable risk factors. It's not druggable the way that this amyloid beta protein is druggable. I think the worst thing about it is that anybody who would advance an alternate viewpoint over the past couple of decades would be ridiculed and silenced by the quote, amyloid mafia. This happened to me. When I first started doing my documentary, Little Empty Boxes, which when I first started doing it, it had a different name. I called it, it was called Breadhead. I can talk about why I named it that, but that was always sort of a working title for the project. Somebody at one of these foundations, right? There's all these big Alzheimer's foundations. I'm lucky to be working on this project with one who really believes in me in the project, the Alzheimer's Foundation of America, but there are these other nonprofits that really what they are is just like a front for perpetuating the status quo and keeping the funding pipeline open for drug discovery. When I first got started working on this on my film, I did a Kickstarter campaign for it. One of these quote, unquote nonprofits, right, deeply invested in the amyloid hypothesis, came out and wrote an op-ed in the Wall Street Journal disparaging me and my project and any other alternate sort of viewpoint and talking glowingly about that adjacana map drug, which at the time had yet to be approved. It was so painful to me at the time because I was working on this project out of the love and passion that I had for my mom and my desire to get the science out, to catalyze interest in this science. It takes 17 years on average for what's discovered in science to be put into day to day clinical practice. I was like, that's time we don't have to lose when the brains of our loved ones are at stake. I was directly sort of in the crosshairs at the time for this amyloid mafia. I was directly affected by it. Because this medication is profitable. Yeah, because the medication is profitable and that the whole avenue was thought to, if you could find a drug that would reduce amyloid burden in the brain, that's going to make shareholders really happy. This drug, is it still being prescribed? Yeah, it's approved. It's approved. There's no real way of telling how many people have died from this drug because most of the people that are taking this drug already experiencing this neurodegenerative disease and you could easily chalk it off to that being the cause of death. Yeah. I can't speak to people's experiences on it currently, but I do know that the trials were... If I had a loved one based on what I know about this drug and those trials, my loved one currently would not be on that drug. They would be perhaps experimenting with... This is a very difficult sort of road to go down. I guess it's easier to say if I had dementia. If I myself had dementia, I would be experimenting with a ketogenic diet on myself and other ketogenic therapies because ketogenic diets, what they do... As I mentioned, in the Alzheimer's brain, the ability to generate energy from glucose is reduced by about 50%, 45, 50%. Its ability to generate energy from ketone bodies is unperturbed. The idea is that a ketogenic diet can essentially keep the lights on in the Alzheimer's brain. It's not a cure, but there has been research on patients with Alzheimer's disease, mild to moderate Alzheimer's disease, that a ketogenic diet intervention can actually improve functional capacity in those patients, which is everything.