The Strange Case Of The Man Immune To Alzheimer’s

0:00And now a word from our sponsor South by Southwest London. Imagine a future where things just make sense. In the 1700s, we had canals. In the 1800s, the railways. Then telecom, fibre optic. And now? In a world that's more unsure than ever before, we need the answers. South by Southwest London presents over 900 speakers, 200 music artists, and 100 films in one location in June. To find out how they merge together and shape the future in person, visit southbysouthwestlondon.com. That's S-X-S-W-L-O-N-D-O-N-D-O-T-C-O-M. Today I want to talk about a really fascinating man called Doug Whitney. He has a gene which causes early onset Alzheimer's.

0:40It strikes from around the mid-40s, but he's 76 now, has no memory problems, no other symptoms of Alzheimer's. Other members of his family, very sadly, have died, but Doug is immune. And scientists have spent years putting him through dozens of different tests to try and find his secret in the hope that, you know, it might lead to the discovery of preventative strategies or treatments for Alzheimer's. And for a while, scientists tried to look at genetic protective factors that he might have. But now we seem to have an answer. From New Scientist, this is The World, The Universe and Us. I'm Dr. Rowan Hooper, joined today by Alice Klein.

1:21Alice, the answer to this mystery seems to be that Doug Doug used to be a mechanic in the Navy and worked in the engine room, the very hot engine room of ships. Yeah, so this is one of the most compelling possibilities that's currently being explored. Whether Doug's long-time work as a mechanic in these super hot engine rooms of Navy ships may have had some kind of protective effect, since it does tie with emerging evidence of the benefits of hot saunas for warding off Alzheimer's. Wow, I haven't heard of hot saunas for warding off Alzheimer's. But let's go back and first explain why Doug, why we thought Doug was certain to get Alzheimer's.

2:00Yeah, so he comes from this family in the US that carries a mutation in a gene called pre-senilin-2, which basically means that proteins in their brains, specifically amyloid and tau, don't fold properly. And they eventually form these clumps that cause the Alzheimer's symptoms. Yeah, those characteristic protein misfolded amyloid and tau proteins. So is that similar to how Alzheimer's develops in other people like the not early onset Alzheimer's, normal Alzheimer's? Yes, yes. People are not part of this family. The difference in this family is that the mutation seems to kind of fast forward the misfolding of amyloid and tau so that the condition ends up emerging at younger ages, usually between the age of around 44 to 53.

2:47And in fact, at this stage, Whitney is the only known carrier of this mutation who has gone well past the expected age of onset without developing Alzheimer's. What a terrifying thing to have hanging over you, hanging over this family and knowing that so many are going to develop this devastating condition that's got no cure and you'll get it at a young age. Yeah. I mean, it's really tragic. So Whitney's mom died of early Alzheimer's as to 10 of her 13 siblings. His old brother has now died of it too. So Whitney has understandably described it as a plague in his family. And he has a cousin called Gary, who's written a book called The Thousand Mile Stare, which refers to this vacant look that people in their family start to get in their forties as the disease takes hold.

3:33Wow. And Gary's got this memory of being at this big family get-together that he and Doug went to as kids and how it was really unsettling because his dad and aunts and uncles were all kind of acting weirdly, but he didn't know why at the time because no one in the family talked about it. Wow. I bet they didn't. Do we know where the mutation comes from? So it's not known exactly where or when it emerged, but it has been traced all the way back to some of the family's ancestors who lived in a small vulgar German village all the way back in the 1700s before they later immigrated to the US around the late 1800s.

4:11Wow. Okay, so look, Doug is quite well known among geneticists really because he's the only known carrier of this mutation who has managed to dodge developing Alzheimer's and that's made him so basically popular amongst Alzheimer's scientists, hasn't it? Yeah, he's hugely interesting. And scientists have been studying his family since, all the way actually since the 1980s, when one of his aunts approached some Alzheimer's researchers to ask them to find out basically what on earth was happening to their family. But Whitney himself, Doug, he only agreed to have the test for the genetic mutation when he was 62, because by that time, he assumed that he must be one of the lucky ones who hadn't inherited the mutation since he had no symptoms.

5:01So of course, that meant it was in a huge shock to find out that he did actually have mutation. And his doctors tested him three times because they couldn't believe it either. And of course, since then, they have been super interested in trying to find out how he has seemingly escaped his genetic fate. Yeah. So they've been looking for any protective effects, genetic protective elements that he might have. But until now, we haven't found what his secret might be. Yeah. So, I mean, there have been some possible genetic clues because he has variants of some other genes that are different to those of his affected family members, which are thought to may play a role in Alzheimer's disease.

5:45But it's a real maybe at the moment. At this stage, there's no really clear genetic explanation for his Alzheimer's resistance? We'll come on to the answer in a minute. But this idea that there is genetic protective effects is really fascinating. There was this famous guy in New York in the 70s and 80s called Steve Krohn, and he was exposed to HIV. He says it must have been countless times. He saw, sadly, many of his friends die. It was the first few years or decades of the AIDS epidemic, but he never got ill. He didn't catch AIDS. He was finally tested and his cells were found to be immune to HIV.

6:30And he had this mutation on his white blood cells that prevented the virus getting in. And I was working on this book, Superhuman, a few years ago, and I met a geneticist who calls these cases inflated airbags. And that is the airbag, The inflated airbag is a protective factor that's been deployed like an airbag in a car crash that has saved you from a disease. So in Steve Crohn's case, the airbag was this mutation that stopped HIV getting in. And people thought Doug Whitney also had an airbag, this genetic protective element that had stopped him getting Alzheimer's. But as you say, they've not been able to find it.

7:10And now we know we think it's not there. And there's an environmental factor that's protected him, and that's the heat exposure he had when he was a mechanic. So take us through that a bit more. Yeah, so one of Whitney's neurologists, Randall Bateman, was at this Alzheimer's conference a few years ago. And a researcher from the French National Science Research Agency, a guy called Geoffrey Canet, gave a talk about the potential protective effects of heat exposure against Alzheimer's disease, which he had been studying in lab mice. And that caught Bateman's attention because he knew that Whitney had worked for two decades as a mechanic in really, really hot engine rooms of Navy ships.

7:53So it kind of got him thinking and he approached Kenei and discussed Whitney's case with him. And since then, Kenei has been studying the potential role of heat exposure in Whitney's Alzheimer's resistance. Wow. I mean, what a kind of mad coincidence that he has the gene for early onset Alzheimer's, but he also happened to work in this environment that might have protected him. What sort of temperatures are we talking about in these engine rooms? He worked in steam propelled ships where the engine rooms can get up to 50 degrees Celsius, which I mean, I just can't imagine working in an environment like that.

8:30And he was sometimes in there for hours at a time. And sometimes he got so hot that his colleagues actually had to hose him down. I'm sure we don't have that sort of level of heat in ships these days. So what do we know about why heat exposure of that kind might protect against Alzheimer's? Well, when you're hot, your body starts to produce these proteins called heat shock proteins that can repair and refold other proteins that might be damaged by that heat. So Kene's thinking is that heat shock proteins might help to keep certain brain proteins in check so they don't get all misfolded and clumpy and lead to Alzheimer's disease.

9:08Okay. And does Doug have more of these heat shock proteins than people who haven't worked in the engine rooms of ships? Yeah. So as part of all the tests that he's had, his cerebrospinal fluid was tested. That's the fluid that surrounds the brain and spinal cord. And that showed that he has really unusually high levels of these heat shock proteins. Wow. And he's also had lots of brain scans, which show that his tau proteins are pretty normal, whereas his affected family members who've got this mutation, they have lots of abnormal clumps of tau spread all through their brains, which is causing their symptoms.

9:44What about amyloid, the other one? So tau and amyloid are normally the proteins that go wrong, aren't they? Yeah, so that is one of the weird things about this case because the brain scans of Whitney's brain show that it's actually chock full of misfolded amyloid. So it doesn't have much tau, but it's got lots of amyloid. But as we've previously discussed on this podcast, it is increasingly being recognised that amyloid is not actually the key driver of Alzheimer's symptoms, as was long thought. And it seems like tau is more of the problem. There is a lot of chat and influencer chat about the health benefits of saunas being in a sauna, not just the sort of the Finnish, you know, lifestyle.

10:30It's nice to be in a sauna, but like it has like loads of health benefits, including Alzheimer's. You know, is that evidence? Is this helping to support that? Yeah, well, some big epidemiological studies in Finland have found that people who go to saunas a lot, like four to seven times a week, are about 65 % less likely to get Alzheimer's than those who only go once a week. And you can only compare to once a week in Finland because there's no one in Finland who goes zero times a week. And then Kane, like in his studies, he's found that if he puts mice in these little miniature mouse saunas that he's made, it actually helps to keep the tau proteins in their brains in the correct shapes, stops them from misfolding, and it promotes tau clearance from their brains so that it can't clump together.

11:18And that might explain why the engine room heat in Whitney's case and the sauna heat for the Finns both seem to have been protective. I mean, this is amazing. I guess if I thought about it, I would have said saunas have this lovely communal aspect that has its own benefits, but there's this direct effect of the heat, the physiological effect. It's amazing. We should all be going to saunas more, right? Yeah. I mean, I have to admit, I used to be quite skeptical about saunas. I just thought they were the latest health fad, like, you know, the whole jumping in ice water was before this. But a very well respected Australian Alzheimer's researcher that I interviewed for this story, Rebecca Nisbet, told me that she now regularly goes to a sauna herself because of all this evidence that is coming out.

12:12So I've actually now been inspired to jump on the bandwagon and my husband is currently drawing up plans to build a sauna in our backyard. Really? In Australia? Okay, so in winter only. You can't use a sauna in Australia. I mean, Finland, yeah, but okay. Wow, that's amazing. So does it mean that cold is bad if hot is good for protecting against Alzheimer's? Yeah, well, interestingly, tau proteins in the brain do seem to be quite temperature sensitive and they do seem to have a tendency to become misfolded in the cold. To the point, actually, that Alzheimer's researchers have to be really careful to make sure their lab mice don't get too cold when they're under anesthetic because it can mess with their tau and therefore mess with their results.

12:57And something that I've discovered recently, which I find really fascinating, is that when bears hibernate in the cold winter, the tau in their brain goes so haywire that it's almost like they have human Alzheimer's. But then, you know, when they wake up again and warm up, it somehow resolves again. Wow. Just more fascinating stuff about hibernation, which is in itself an amazing thing. But this does make me think I should live in Australia or in another really hot country. Well, you might be onto something there because some of the places in the world that have unusually low rates of Alzheimer's disease are very hot.

13:38There's a town in India called Balabgar that has the lowest measured rate of Alzheimer's in the world in people over the age of 65. So I went and looked up its weather and I saw for three days next week, it's predicted to be 48 degrees Celsius. Oh, wow. And it's getting hotter because of the climate crisis, but maybe this is a sliver of benefit from it that it has this protective effect. I mean, that's still almost unlivable to get that hot, but how extraordinary. And then there's another place that I found with unusually low Alzheimer's rates, which is the Bolivian Amazon. And, you know, we all know that that's very hot and steamy, like kind of like a sauna.

14:20and of course obviously there's there's other reasons contributing to the low rates of Alzheimer's in these places like it might be their different diets or levels of physical activity but it is possible that the heat is one factor and I think this is really interesting because you know you say that Australia is really hot but so many people here live in very cold air-conditioned boxes and it's the same in the US it's increasingly like that in the UK but a bit of heat might actually be good for our brains. Wow. What I've taken away from this story is just how complex these kinds of diseases are.

14:55And, you know, in the olden days, we used to think that there might be a, you know, a simple genetic protective effect. And with Doug, that was a really compelling idea, like with Steve Crone. So in some cases, it is. Steve Crone had genetic immunity, one one mutation which made him immune to HIV. But in general, things are much more complicated. Like genetics are a major determinant of health, but we must always remember there's all these other reasons why people get sick and environmental reasons and also how they can be protected and treated. That's all for this episode. Thanks to our guest, Alice Klein.

15:33Thanks to you for listening. Do subscribe and follow wherever you get your podcasts. Bye for now.

15:41Thank you.