Why amyloid isn’t the whole story; vascular hypothesis

1:11:18common cause of dementia, 60 to 70% of all cases of dementia are Alzheimer's. Globally, there's about 50 million people living with dementia right now in 2021. And if we look at a 2050 projection in the future, right, people are living longer. And if people are living longer, these age related diseases are going to go up. And so by 2050, there's projections of 100 to 150 million individuals globally. That's nearly triple of today living through these symptoms. >> Okay. Black Americans are two times more likely. Hispanic Americans are 1.5 times more likely. Women make up approximately

1:11:592/3 of the US Alzheimer's population. Yeah. >> And nearly twice the risk, lifetime risk versus men at the age of 65. So there's a lot of these disparities that go on. We still don't know much about why. I mean, you can imagine economic and social issues, diet issues with like black Americans and Hispanic Americans versus white people who just I mean, they're in a different economic bracket on average, right? So, these on average statistics comes through and it's it's a big like crisis in medicine to figure out what is going on and how do we help it. >> It was first identified in 1906 by by Dr. Alloys Alzheimer. He was a German doctor. um he identified these

1:12:40extracellular amyoid plaques in patients with dementia and since then we've been studying these things called amyoid plaques. The idea is you've got this accumulation of a protein called beta amyoid. Okay, there are these peptides and that's the primary cause. You get a bunch of amyoid precursor proteins. So this is whatever is the precursor to amyoid. They denature in some way and they get together, right? And when they get together, they create these plaques of amioid and those plaques then get in the way of all of the neural machinery.

1:13:20>> I get I get it's there's a highway and then these these roadblocks just >> Yeah. start autogenerating and blocking the flow of stuff. >> Yeah. And there was genetic link, right? because early onset familial Alzheimer's um was caused by mutations in this protein in the gene for this protein. >> Got it. >> So you can imagine okay that seems like something that we should target. >> There was a big discrepancy between targeting this pathway and actual clinical advantage. Okay. >> Okay. The drug failure rate the drug failure rate from 20 2002 to 2012 is something like 99.6% 6% and even today

1:14:00like this is a headline from last year. Nova Nordisk shares plunge after the Alzheimer's drug trial fails to hit the key target. >> Interesting. >> Okay. So there's so much research that is going into Alzheimer's, but when we try stuff in animal studies, when we try stuff in a petri dish, and then when we go in and try to fix the ammyoid crisis in the brain of patients, it doesn't quite work. There's only a weak correlation. It turns out the more of the research we do, there's only a weak correlation between the total plaque load in the brain and cognitive severity because the more and more that we've been able to do brain scans of healthy patients, >> we figured out that some of these healthy patients >> have a myoid plex. >> So that can't be the whole story.

1:14:42>> It's not it's not a single source. It's not the single source of the problem. Yeah, >> it it may be part of it. >> Yeah. But it can't be that oh a myoid plaque one direction causes Alzheimer's because there's plenty of people that have amyoid plaques that don't have Alzheimer's. Okay. >> Furthermore, there's a timing problem because the amyoid plaques, they start accumulating like 20 years before the actual symptoms. So by the time you've got the symptom and you're trying to treat this thing, it's like the forest fire is already starting. >> Yeah. Yeah. Okay. Yep. That tracks. And so there's been recent approval of certain um drugs, but it only shows a modestly slow decline in early stage patients, but it's not a cure. It

1:15:23doesn't reverse the effects of Alzheimer's right? >> And sometimes it carries risks like brain swelling and hemorrhage. So this amoid paradigm is really under pressure, right? And we need to find a new way to figure out what's going wrong in Alzheimer's brains and is there a way to reverse the effects? not just stop, not just slow down, but reverse. >> Because I mean, even just looking at this this data, the drug failure rate that you mentioned of 99.6% was across, you know, almost over 200 programs >> um in a in a 10-year time span. So, it's not like there if it's from a lack of trying. >> No, no, it's like we're trying, but like the fundamental issue we're having is maybe the philosophy with which we're

1:16:03going about >> right this. >> If if you're the Dallas Cowboys and you're like, why haven't we been to the playoffs in 30 years? It's like you're looking at everything but the source of the problem which might be you know anyway or if you're Ferrari. >> Yeah. >> Never mind. That's a that's a source for another day. >> Yeah. I don't want to get into that. We're doing well. It's going to be fine. Anyways, so we need to change the way that we're approaching this problem. Right. >> Okay. So now let's think about the brain from a mechanistic sense. >> Okay. >> The brain is only about 2% of the body mass. >> Mhm. >> But it uses up 20% of the body's energy.