The Radical Theory That Could Force Us To Rethink Alzheimer’s

0:00When you want your spring break to feel like and your kid's pool day to feel like and your hotel bed to feel like and room service to feel like because at Hilton, hospitality feels like Your cabana's ready. Would you like fresh towels? It matters where you stay. Book now at Hilton.com. Hilton, for this day. Alzheimer's disease is the most common form of dementia which is the leading cause of death in the UK the joint top cause in Australia and the fifth most common cause of death in the United States It's a terrible disease and we've thought for over 100 years that Alzheimer's is something that starts in the brain something goes wrong in the brain and then it leads to dementia but now there's compelling evidence that Alzheimer's in fact begins in places like the skin, the lungs or the gut it begins outside the brain and it spreads to the brain and there it forms these characteristic misshapen proteins but the idea that it starts outside the brain is radical stuff it could really upend our understanding of the disease that's what we're getting into on this episode of the world the universe and us from new scientist i'm dr rowan hooper i'm joined by reporter alice klein hi alice look it seems heretical to say this about alzheimer's because we've always thought of it as a disease that starts and ends in the brain.

1:28So what's the basis for this like radical rethink? Yeah, well, obviously, all the main symptoms of Alzheimer's disease are brain related. You've got memory problems, confusion, personality changes, and so on. So it seems like purely a brain thing. And for a long time, the dominant view has been that Alzheimer's is caused by, as you said, a buildup of the amyloid and tau proteins in the brain. and then that leads to memory problems and so on. Yeah, so those two misshapen proteins, the sticky plaques that are characteristic there, the beta amyloid and then the tangles that you see in the brains of people with Alzheimer's, that's the second protein called tau protein.

2:06Yes, but then all this effort has gone into making drugs to clear out amyloid and tau. And they do this very effectively, but this doesn't seem to mean much for Alzheimer's patients. You know, they're not getting much better even when those clumps of amyloid and tau are all cleared out. And so this is what has led some neuroscientists to start thinking outside the box. Yeah, but they've had to, haven't they? Because research has been going on for decades, focused on those two proteins, trying to remove them or break them down in a way to try and treat Alzheimer's. But as you say, it's only had limited success.

2:38And so we've had all this huge effort and we've only got a very small number of drugs that can do it and they don't really seem to work. but what we did report something really radical about alzheimer's a few years ago maybe 10 years ago now when scientists found a link between gum disease and alzheimer's and that was where the infection that causes gum disease it kicks off an accumulation of of those bad proteins of the misshapen proteins in the brain the disease is peridodontitis it's a this chronic gum disease it's caused by a bacterium called porphyromonus gingivalis and what it looks like is that toxins from that bacteria, they go from the mouth into the brain and that causes inflammation.

3:20And that's what causes these amyloid beta plaques. And then you get the cognitive decline. Yeah. And there's work showing that you can see this early on by looking at the composition of bacteria in people's mouths. So people with memory problems in their 50s have more of this bacteria. And I'm not going to try to say that like you, Rowan. Is there a theory that the brain is using these proteins is a way to try and protect itself against attack. Can you tell us about that? Yeah, so some neuroscientists have been wondering whether these proteins actually form in response to the disease, you know, perhaps to trap or defend against bacteria or virus or toxins that get into the brain.

4:01And in fact, some scientists have grown mini brains in dishes and then added herpes virus and found that the mini brains develop amyloid plaques that are reminiscent of those seen in Alzheimer's. oh wow i did not know that so they've infected mini brains with a sort of proto alzheimer's like disease yike yeah i mean that's better than infecting a mouse with i suppose and you can learn a lot that's why we have mini brains we're leaving today and entering a world of mickey mouse waving princess meeting and greeting lightsaber clashing the twilight zone tower of terror dropping banshee flying space mountain launching galaxy rewinding what's the book galaxy rewinding fireworks igniting world of other worlds for whatever you love infinite worlds await at the most magical place on earth walt disney world resort i guess the big question is what is actually causing the alzheimer's then you know other what we're saying then is that the protein these misshapen proteins might be a side effect or a response to the condition rather than the condition itself, a trigger.

5:13Yeah, so that's what some researchers are now investigating, especially because, you know, some people have Alzheimer's with no amyloid and tau, and then some people have a lot of amyloid and tau, but no Alzheimer's. Well, I didn't know that either. Some people have Alzheimer's with none of these misshapen proteins and then some have loads of them but no Alzheimer's. Wow. Yeah and so it was actually recently found that 30 % of old adults have their brains are so full of amyloid or tau that they would technically qualify for an Alzheimer's diagnosis but they don't have any signs of the condition.

5:47They don't have memory problems, nothing and this is what's really forcing a rethink on what causes the condition. You know this is why a research group at a Novo Nordisk research center in Copenhagen decided, okay, let's just go back to the drawing board and start again. And they did what's called a genomic analysis, where you look across the whole genomes of thousands of people with and without Alzheimer's disease to find out which kinds of genes are actually involved in the disease. And then they also looked at gene activity in 5 million single cells from 100 different regions in the brain and also 40 areas around the rest of the body.

6:26Yeah. So they did a very thorough job. You know, I really like that they kind of wiped the slate clean, assumed no prior knowledge about what the disease was and just kind of started again. So what have they found? So the funny thing was that they looked at the expression of a thousand so-called Alzheimer's risk genes. So that means genes with variants that give you a higher risk of developing Alzheimer's disease. And at first they thought they must have actually graphed it wrong because these risk variants weren't very active in the brain at all. They were much more prevalent in other areas of the body, like the skin, the lungs and the gut.

7:01So that was the sign that Alzheimer's probably doesn't start in the brain because the genetic variants that make you more likely to develop it, they're not really being expressed much there. Yeah, that's right. Okay. So where in the body is it starting? Well, this is the big mystery, But one big clue is that many of these Alzheimer's risk genes are known to be involved in immune regulation. And they also tend to be in what are known as barrier tissues. So these are things like the skin and the lungs and the gut, which are regularly defending against germs and toxins and allergens by mounting inflammatory responses.

7:39Yeah. And the gum as well. Like we mentioned before, like the gum is like a critical barrier tissue, isn't it? And if you get infected there, then that's why it can perhaps cause problems and be really vulnerable to that kind of disease. Yeah, definitely. Although this study didn't actually have access to mouth or gum samples. So I have asked them if maybe that could be their next study. Yeah, they should. Are they going to do that? Well, they said they're interested in it. Make sure you have your name on the paper if they do that. I should. No, they said we hadn't thought of that yet. Yeah, that's great.

8:11Please do this. But, you know, so this made the researchers think. OK, so maybe if you're someone with a family history of Alzheimer's disease, maybe you inherit these genetic variants that cause you to have a certain inflammatory response when you get, say, a virus in your lungs or cold sore in your skin or something. And then somehow, we don't know how yet, that inflammatory process damages your brain and might lead to Alzheimer's disease. OK, so just let's have a recap on inflammation, because it's such a key to so many things in our bodies, isn't it? And effectively in our lives. So inflammation is when the immune system goes up to 11.

8:48It turns it right up. It goes up too far. It's a thing we want in many ways. So if you say you cut your hand, that sore bit, the flared up bit around the cut in your hand, that's inflammation. And it does that to fight off any bacteria that's in the wound. So that's a short term thing. But if you have persistent inflammation, that's when it can lead to all sorts of nasty problems, including cancer, heart disease. strokes, arthritis, stuff like that. Yep, and also mental health conditions such as depression and anxiety. Time for a quick message. In the world of high-stakes science, some challenges are just too big to tackle alone.

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10:10So what about the blood-brain barrier though? That's this critical barrier that is supposed to really shield and protect the brain from the rest of the body and stop this sort of thing, stop nasty stuff getting to the brain. Yeah, I mean, and this has been the thinking for years that the brain is like this separate protected entity in the body. But actually, there's more and more research coming out now to show that this is not really the case, and particularly in the case of inflammation. So we now know that when you have an infection or something anywhere in the body, you get this inflammatory response where immune cells like T cells are activated, you get signaling proteins called cytokines being released, and these can actually circulate through your blood, cross the blood-brain barrier, and then cause damage inside the brain.

11:00And what's been the response to scientists, Alice, that you've spoken to? Because, you know the way you've we've been talking about it seems really reasonable but it is we have to remind ourselves it is really radical isn't it so how are people taking it yeah i mean the the lead scientist who did this study caesar kunha told me that he's faced a lot of resistance uh to this reframing of alzheimer's disease and at conferences he's had people telling him well if you're not studying amyloid you're not studying alzheimer's um which is a bit harsh but then other neuroscientists I spoke to for this story, they were actually surprisingly receptive to the idea because they pointed out that there are a lot of different threads of research that now seem to be pointing this way.

11:43So it is becoming harder to dismiss. Yeah. And like, I mean, it's like other big problems in science that you try one way for many years and you need to start looking at new approaches in order to find a new way in. So look, we talked about gum disease already, but there's lots of other things that have been linked to Alzheimer's over the years, aren't there? Like we mentioned diabetes. What else? Yeah, so I mean, there are many different conditions that seem to be linked to it. And this has been kind of confusing for a long time because you've got all these different things like eczema, cold sores, gut infections, lung infections, sexually transmitted infections, so on.

12:23And they all seem to make people more at risk of getting Alzheimer's disease down the track. And that new study kind of helps explain that because they're all, maybe they sort of start to get through the barrier that you're talking about. Yeah. So all of those things involve inflammation in various different parts of the body, which, as we've discussed, could then potentially damage the brain. And something that I find really interesting is that epidemiological studies show that those infections and inflammatory conditions are most strongly associated with Alzheimer's disease when they occur in the sort of midlife period, so around people's 50s.

13:03Okay. I'm just laughing because I happen to be around that period. So that is interesting because we know that the disease, it can begin decades before the symptoms come along. So does that mean that this middle age period is a really critical time? I need to be careful. Yes, you are in the critical window, Rowan. Yeah, so this new genomic study did find that these Alzheimer's risk genes seem to peak in activity between the ages of 55 and 60. So, you know, that might be this critical window in your life where if you catch pneumonia or something, it's more likely to set the stage for Alzheimer's disease.

13:43Wow. And, you know, this is speculation at this point, but we do know that most people don't seem to get Alzheimer's until their 70s or 80s, but we're not really sure why there's that time lag. So what can we do if you're in that critical period, midlife period, to lower your inflammation levels and try to sort of prevent yourself from getting this nasty, horrible thing down the line? Well, there's some really interesting research coming out now showing that people in their 50s who get the shingles vaccine or another one called the BCG vaccine, which was originally developed for tuberculosis, but it's often given to bladder cancer patients.

14:24So if you have either of these two vaccines around the age of 50, then you appear to have a much lower risk of developing Alzheimer's disease. Like for the shingles vaccine, it's a 50 % risk reduction. Wow. Which is, yeah, pretty amazing. And one neuroscientist that I spoke to for this story, Donna Wilcock, said maybe this is because midlife vaccination gives the ageing immune system sort of a wake-up jolt so it works better and there's less inflammation. So this is a really intriguing and promising lead because we get most of our vaccinations in childhood but you know maybe we should be getting more when we're older as well.

15:00I'm actually going to think about trying to get a shingles vaccination because why not? You know it's a fantastic insurance. What about diet and other lifestyle things? Well, over the years, we've had so many stories in New Scientists about things that you can do to protect yourself against Alzheimer's disease. And these things include things like eating a Mediterranean diet, exercising, keeping your blood pressure and cholesterol in check. And actually, what all of these things have in common is that they reduce inflammation. Everything's coming back to inflammation, isn't it? It's just so critical.

15:33and then another thing of course is i remember from the last story is flossing taking really good care of your oral hygiene and and making sure that that gum bacteria doesn't cross over and we've also talked on the podcast before about the link between inflammation and aging inflam aging it's called and that's when microbes from microbiome get into our bloodstream and that triggers inflammation that are sort of on a on a chronic level and has a like a gradual wearing out effect on ageing effect on the rest of the body. Another thing you mentioned in the write up of this, Alice, is that all this reframing of Alzheimer's is a bit like how obesity has been reframed in the last few years.

16:14And that has led to better treatments. And can you talk a bit about that? Yeah, sure. So in the past, when scientists were trying to develop drugs for treating obesity, they were mainly focusing on making drugs that directly targeted the excess fat tissue, you know, because that kind of makes sense, but they didn't work very well. And then these genomic studies started coming out showing that, well, actually the gene variants associated with obesity tend to be more in the brain and affecting things like appetite and energy regulation rather than in the fat cells themselves. So then Novo Nordisk developed the weight loss drug semaglutide, you know, which we all know as a Zempick and Weggev, which target those brain pathways instead of actual fat tissue.

17:01And obviously that has been revolutionary. So now in the case of Alzheimer's, we've also been trying to treat the end result of the disease, you know, the final brain pathology, but maybe the root causes are somewhere else in the body, you know, potentially inflammation in the skin or the lungs or whatnot. And actually we need to be concentrating on those instead. Okay. That's amazing stuff. Thanks, Alice. We'll leave it there. That's all right. This is The World, The Universe and Us from New Scientist. I'm Rowan Hooper. Thanks for listening. Do follow on our new YouTube channel and we'll be back soon.

17:31Bye for now.

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