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

0:00This episode is brought to you by Focus Features. On March 27th, Focus Features invite you to be a part of the most explosive movie of this year's Sundance and South by Southwest Film Festival. The AI doc or how I became an apocalypticist is being called supremely entertaining and the most urgent movie of our time. The AI doc or how I became an apocalypticist rated PG-13 only in theaters March 27th. 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 a hundred years that Alzheimer's is something that starts in the brain, something that goes wrong in the brain and then it leads to dementia. But now this 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 mis-shape and proteins.

1:03But the idea that it starts outside the brain is radical stuff. It could really up-end our understanding of the disease. That's what we're getting into on this episode of the world the universe and us from new scientists. I'm Dr Ron 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. So what's the basis for this like radical rethink? Yeah well obviously all the main symptoms about 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 build up of the amyloid and tail proteins, the brain and then that leads to memory problems and so on. Yeah so those two mis-shape and 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 a second protein called tail protein.

2:05Yes but then all this effort has gone into making drugs to clear out amyloid and tail 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 tail 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 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 and 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 those bad proteins, the mis-shape and proteins in the brain. The disease is peridodontitis, it's a chronic gum disease, it's caused by a bacterium called porthoromonus gingivalus and what it looks like is that toxins from that bacteria they go from the mouth into the brain and that causes inflammation and that's what causes these amyloid beta plaques and then you get the cognitive decline.

3:25Yeah 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. Is there a theory that the brain is using these proteins as 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 to perhaps to trap or defend against bacteria or virus or toxins they get into the brain. And 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, yeah. I mean that's better than infecting a mouse without a spouse and you can learn a lot that's why we have mini-brains.

4:26My day kicks off with a refreshing Celsius energy drink, then straight to the gym, pre-gift pick up, back home to meal prep, time for my fire session shift. One more Celsius gotta keep the lights on. When the three alarm hits I'm ready. Celsius, live, fit, go. Grab a cold refreshing Celsius at your local retailer or locate now at Celsius.com. 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 mis-shape and proteins might be a side effect or a response to the condition rather than the condition itself or trigger. Yeah so that's what some researchers are now investigating especially because you know some people have Alzheimer's with no amyloid and towel and then some people have a lot of amyloid and towel but no Alzheimer's. Well I didn't know that either. Some people have Alzheimer's with none of these mis-shape and proteins and then some have low to them but no Alzheimer's wow. Yeah and so I was actually recently found that 30% of old adults have their brains are so full of amyloid or towel that they would technically qualify for an Alzheimer's diagnosis but they don't have any signs of the condition, they don't have memory problems, nothing.

5:40And this is what's really forcing a rethink on what causes the condition. You know this is why a research group at a Nova 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 five million single cells from a hundred different regions in the brain and also 40 areas around the rest of the body. Yeah so they did very thorough job. Yeah I really like that they kind of wiped the slate clean assume 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 gene so that means genes with variants that give you a higher risk of developing Alzheimer's disease.

6:40And at first they thought they must have actually graft 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. So 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. Yeah 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.

7:44Yeah 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 you know. Yeah well make sure you have your name on the paper if they do that. I sure know they said we hadn't thought of that yet. Yeah that's great. Please do this but you know so this made the researchers think okay so maybe if you're someone with a family history about some of the 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 so on 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. Okay 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 it 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 saw bit the flare the flare up bit around the cut in your hand

8:51that'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. Yeah 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. That's why researchers from the UK and Spain have teamed up to rethink the entire life cycle of our medicines. Funded by the Horizon Europe Research and Innovation Program the Eternal Project brings together Spanish tech leaders like Iris Technology Solutions with UK giants like AstraZeneca and quotient sciences. They're using digital twins and laser technology to find ways of slashing chemical waste and energy use in drug manufacturing. As Dr. Laura Rodriguez from Iris puts it, having the UK's expertise on board is crucial to achieving these green breakthroughs.

9:54Find out more in the full new scientist co-lab feature article sponsored by the UK government at new scientists.com slash eternal. So what about the blood brain barrier though? That's the 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 across the blood brain barrier and then cause damage inside the brain. And 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.

11:02So how are people taking it? Yeah I mean the lead scientist who did this study sees a Kunha told me that he's faced a lot of resistance to this reframing of Alzheimer's disease. And at conferences he's had people telling him well if you're not studying the amyloid you're not studying Alzheimer's. 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 seem to be pointing this way. So it is becoming harder to dismiss. Yeah and unlike I mean it's like other big problems in science that we you try one way for many years and you need to start looking at new approaches and 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 sauce, gut infections, lung infections, sexually transmitted infections so on.

12:15And they all seem to make people more at risk of getting Alzheimer's disease down the track. And is that 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 you know 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 both strongly associated with Alzheimer's disease when they occur in you know the sort of mid life period so around people's 50s. Okay I'm just laughing because I happen to be around that period. So that is interesting because we know that the disease it begins decades before 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.

13:17Yeah 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. 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 mid life period to lower your inflammation levels and try to sort of prevent yourself from you know getting this nasty horrible thing down the line. Well there's some really interesting research coming out now showing that people in their 15s 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. So 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.

14:27Wow which is yeah pretty amazing and one neuroscientist that I spoke to for this story to Donna Wilcock said maybe this is because mid life vaccination gives the aging immune system sort of a wake up jolt so it works better and there's less inflammation. So this is a really intriguing 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. I actually going to think about trying to get as shingles vaccination because why not you know it's 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 and check and actually what all of these things have in common is that they reduce inflammation. Things coming back to inflammation isn't it. It's so it's just so critical and then another thing of course is I remember from the last series flossing taking really good care of your oral hygiene and making sure that gum bacteria doesn't cross over.

15:36And we've also talked on the podcast before about the link between inflammation and aging inflammation it's called and that's when microbes from microbiome get into our blood stream and that triggers inflammation at a sort of on a chronic level and has a like a gradual wearing out effect on aging effect on the rest of the body. And another thing you mentioned in the in the right 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 and 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 on making drugs that directly targeted targeted the excess fact issue you know because that kind of makes sense but they didn't work very well. And then these genomic studies study 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.

16:38Rather than in the fat cells themselves. So then Nova Nordisk develops the weight loss drug semi-glutide you know which we all know as a Zempic and Wage of E which target those brain pathways instead of actual fact issue and 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 is somewhere else in the body you know potentially information 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 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 bye for now.