June 16, 2022

Understanding and treating Alzheimer’s

By Conor McKechnie and Dodi Axelson

Understanding and treating Alzheimer’s

In this episode, we contemplate the combatting of the devastating disease that Alzheimer’s is. According to a recent report by the Alzheimer’s Disease International, an estimated 50 million people are living with dementia due to Alzheimer’s disease. We talk to two experts leading two respective early-stage studies into possible treatments for Alzhemier’s. One study looks at the tackling of tau proteins, another looks at treating aging rather than the disease itself.

DODI: There are a few absolutes in life. Taxes is one. Death is another. And for those of us who are lucky enough, ageing is another one.

CONOR: Yeah, so we're between the two. Every minute of the day, every day of the year, every year of our lives we slowly age. But let's not get depressed about it. Let's just agree we should aim to age gracefully.

DODI: Okay, if you say so. Today, though, let's take a closer look at a disease that often comes with ageing, and it's tragic. It's a very difficult one for patients and for families, it is Alzheimer's. And according to the Alzheimer's Association, one in three senior citizens die from Alzheimer's or from another form of dementia.

CONOR: It's kind of really annoying, isn't it? As we get better at treating and curing other non-communicable diseases, such as heart disease, and cancer and so on, Alzheimer's and these other dementias are affecting more and more people. So, it feels like we're beating cancer and now like the eternal video game of life, it's got another boss for us to take on.

DODI: It does. Our brains are tricky machines. So today, we're going to hear from two different experts leading two respective studies for the treatment of Alzheimer's. This is also notably Alzheimer's and Brain Awareness Month this June. So, without further ado, this is what matters on today's episode of Discovery Matters.

SINÉAD: So, my mum, Teresa, was diagnosed with Alzheimer's in 2015. we had started to notice memory changes, unusual memory changes, in her around 2012. It was different changes in her behavior, becoming more erratic about things, hiding things, finding things in unusual places. So, her context and her ability to position things in her mind was starting to go. So, she was diagnosed through the Memory Clinic in St. James's in Dublin through a series of tests, memory tests, an MRI scan, it's quite a lengthy process to get diagnosed with Alzheimer's. And it's a devastating diagnosis. And it felt like the reverse of a child learning: it felt like she was losing her language skills, her abilities, her perception. I always felt so sad for her, that the world around her seems like it was changing. To her the world was becoming an unfamiliar place. And that must be so frightening. And like most people, a lot of people with Alzheimer's or dementia, she just wanted to go home. And fortunately, we were very close to her childhood home. We were able to bring her there regularly. On a couple of occasions where she did wander off, that's where she went. But she really focused on us her family we were her anchors, I suppose her lighthouse, her rocks.

CONOR: A familiar voice there.

DODI: Yeah, this is Sinéad Allen. She is on our comms team. She's our friend and colleague. Sinéad, sadly lost her mother in January of this year.

SINÉAD: I heard somebody say once that through Alzheimer's, you're losing the person that you know and that you love before they've gone. And I think that was the hardest part for us. Seeing mom change, seeing her lose her sharp, fiery spirit, because my mom was a woman who could have commanded armies, and seeing her lose those aspects of her personality that we had known growing up. And we were her anchor in an unfamiliar world but of course, when we were kids, she was ours. So, I'm glad that we were able to do that for her. And looking at all the research that's out there now. We are still very hopeful that something can be found to help stop the progression of Alzheimer's. I know that it's a very slow progressing disease. And I'm in my 40s now, and there's Alzheimer's in the family, so it's possible that my brother and I might have a genetic disposition towards it. It's entirely possible that we don't. But Alzheimer's research is something I always keep an eye on. I'm always very hopeful for and I would love to think that one day, we can do more.

DODI: And it is the experience of individuals like Sinéad that drives research to cure Alzheimer's disease.

DR LUCY VIVASH: I've always been fascinated with the brain from a very, very early age. I can't understand why anyone would want to study anything else to be perfectly honest. It's amazing.

DODI: This is Dr. Lucy Vivash.

DR LUCY VIVASH: I'm a research fellow at Monash University, which is in Melbourne in Australia. And I'm a medical researcher so I am particularly interested in researching neurodegenerative diseases, both imaging techniques to better diagnose them as well as clinical treatments for actually treating patients and preventing or halting the progression of disease.

DODI:Lucy's story starts when she was a child, and she'd helped her grandma who had MS (multiple sclerosis). That influenced her decision to study neuroscience.

DR LUCY VIVASH: I always wondered whether or not I would want to be like my nan and lose my body but keep my mind. Even up to right to the end, she was still sharp as a tac, couldn't see anything and she couldn't move, but she could still completely pull you down a peg or two.

DODI: She ended up at Monash University, studying tauopathies.

DR LUCY VIVASH: So, they're neurodegenerative diseases that are caused primarily by the accumulation of a protein called tau. And the work that we've been doing most recently, we've most recently published, is in a disease called behavioral variant Frontotemporal dementia, which is one of the tauopathies.

CONOR: So that's Frontotemporal dementia. It's shortened to FTD often, right?

DODI: That's right. Lucy says this disease is highly disruptive and very distressing for patients.

DR LUCY VIVASH: It presents with behavioral abnormalities, impulsive behaviors, kind of wacky behaviors, socially inappropriate, kind of sexually explicit, weird kind of food preferences and intolerances and very, very strange behaviors that can be very upsetting for families and for the patients themselves.

CONOR: So, what does her research look like?

DODI: Recently, she and her team have been working on a drug called Sodium Selenate, which acts to reduce the levels of this toxic protein tau in patients with FTD.

DR LUCY VIVASH: So, essentially what happens is the sodium selenate activates an enzyme in the brain that reduces the amount of tau that is in the brain overall and allows the brain sort of natural clearance mechanisms to get rid of the tau. And this then, is preventing further decline in these patients. So, it doesn't kind of roll back the clock, but it certainly stops the clock is the results we're getting so far for a good proportion of the patients that we're really seeing some real strong benefit.

CONOR: Okay, so this sounds exciting how far she got?

DODI: It's early yet. The study that she published was a phase one B study. But right now, she's recruiting for phase two. The great thing is that research shows that sodium selenate can be used for other degenerative diseases.

DR LUCY VIVASH: We're also testing our drugs, sodium selenate in another disease called progressive supranuclear palsy. So, this is a movement disorder that is also caused by tau. Again, it's that same pathogenesis, the same underlying process, the disease just presents in a different way. So, we're really focused on sodium selenate through its actions on tau in actually a suite of different neurodegenerative diseases.

CONOR: So, this all sounds really hopeful as a treatment for early onset dementia. But look this is Discovery Matters, I want juicy details about how Lucy and her team sort of move forward and discovered all of this.

DODI: Sure, let's dig in. Lucy told us that the discovery of sodium selenate actually came through one of our colleagues who was developing it as a treatment for prostate cancer.

DR LUCY VIVASH: So, our upstairs neighbor, Chris, came to us and said, "Oh this PP2A, it's involved in tau and tau is involved in all these neurodegenerative diseases. What do you think?" And so, we though let's have a look into this. It was just sort of a Kismet moment, really, of us being able to say "Well, actually, yeah. This could work. This could really work."

DODI: Lucy says that while amyloid and Alzheimer's are very much discussed. People have been reading about the connection between amyloid and Alzheimer's, it's really being studied, it's correlated. It's also interesting to know that the tau seems to correlate very highly with the actual cognitive decline that Lucy and her team are seeing in patients.

DR LUCY VIVASH: I think there's a big interplay between all of these different proteins and neuro toxic pathologies that are ongoing. So it might be that in the future, you don't get treated for Alzheimer's or FTD, or whatever it may be, with just one drug, but multiple different drugs. And this is sort of where some of the other work I've been doing, looking at better diagnostics, comes in in that we're sort of aiming towards what we like to call precision medicine, which they're very, very good at in cancer, but we're not quite there with neurology yet. So, the idea being that if you have this abnormality, and this protein, and you take this drug, and if you have the abnormality in this protein then you take this drug. So, there might be in the future, the application of combination therapies that are very much personalized to individual patients to really like, actually get at what is driving their disease.

CONOR: Okay, so again, and we've done this a lot in the last few episodes, this is personalized medicine rather than a one size fits all approach.

DODI: Exactly.

CONOR: So, some of the effects of sodium selenate that Lucy has seen from the phase one B study, what are they?

DODI: Yeah, and that's an important reminder that this is early days. But so far, what's great is though mild side effects have been detected, the team hasn't seen any serious adverse effects on the patients who've been using the drug.

DR LUCY VIVASH: So, we're not getting any systemic problems, anything to do with their heart, their kidneys, liver, blood, all that kind of thing.

DODI: When looking at results of this phase one B trial, Lucy could see consistency among the data that made her think, yeah, there's something here.

DR LUCY VIVASH: The real kind of the feather in my cap, the day that I got to show this off to the team, was when we found out there was two patients who had genetic abnormalities, one of which was associated with tau, and one of which was not associated with tau. And the patient who had the non tau related genetic mutation had, unfortunately, not responded to the treatment, which is kind of what we would expect, given the mechanism. But the patient who had the tau associated genetic mutation had absolutely gone great guns. He had done fantastic. So, this really solidified that actually, this was real, you know, if they'd been the wrong way round, we would have been completely done. But this really sort of reinforced the point, then everyone was just "What about...?" and I just got every single possible question that they threw at me. I was like, "No, yep, this is fine. I checked this and I checked that." "What about this?". "I checked that", it was solid. And so that was really good, to be able to just have anticipated and gone through every possible explanation and still, we had something good.

DODI: So, this is one way the future of treatment against Alzheimer's might look. But another way, we could rethink the whole idea of ageing.

DR JOSHUA HARE: There is a concept known as health span, which is that the longer you live, the greater the risk you are for poor health span.

CONOR: So, who's this?

DODI: This is Dr. Joshua Hare.

DR JOSHUA HARE: I'm in Miami, Florida. I'm a professor of medicine at the University of Miami. And I am a co-founder of the biotechnology company Longeveron.

CONOR: And what is their focus?

DR JOSHUA HARE: So, Longeveron was founded with the imprimatur of tackling ageing.

DODI: Well, there's this new paradigm in medicine right now known as the geroscience paradigm.

DR JOSHUA HARE: And the geroscience paradigm holds that ageing is the biggest risk factor for all diseases, whether you're talking about neurologic, cardiac, or cancer.

DODI: Joshua and his team have been thinking maybe there's a new approach that medicine needs to tackle going forward, and that is to actually treat ageing.

CONOR: So, this is kind of like flipping the treatment on its head: tackle the ageing to tackle the disease. So, treat ageing as a disease. Okay.

DR JOSHUA HARE: In heart disease, we know that high blood pressure is a risk factor for heart disease. So, over the years we have developed treatments for high blood pressure as a way to reduce heart disease. So, if we now recognize that ageing is a much bigger risk factor for all diseases, including heart disease, maybe we should be treating ageing the way we treat hypertension. The other example is Alzheimer's disease, right? Alzheimer's disease becomes more and more prevalent as people age.

CONOR: So, this is, you know, part of the modern world's big conundrum, right? We live longer, but the extra years that we're seeing in modern populations aren't always really good quality years.

DODI: Exactly.

CONOR: They could be very low-quality years in hospital and so on.

DODI: Completely. So, looking at frailty, Joshua and his team discovered in an early study that when they measured cognitive function, it was cognitive function in people with frailty, which got better.

DR JOSHUA HARE: So, this was a very, very fortuitous discovery. And it was very exciting to see wow, the cell therapy with Lomecel-B wasn't only improving physical function in frail individuals, it was also producing cognitive improvements. So, maybe, maybe, just maybe, it could have cognitive improvement in people with Alzheimer's disease.

CONOR: So, Joshua mentioned the name of investigational drug there. What's it made from?

DODI: It is made from special living cells called medicinal signaling cells or MSCs, that are isolated from fresh bone marrow tissue donated by adults aged 18 to 45.

CONOR: Okay, so this is the company's lead therapeutic candidate, is that right?

DODI: That's right. That's right. And Joshua says there was a second discovery in the same study that really brought it all together for them. And this came about when he talked to experts in the field of Alzheimer's.

DR JOSHUA HARE: And they also had this wonderful aha moment. And we were told by some experts in the field, this made a lot of sense because of the problems that the Alzheimer's field was having. There is or maybe better to say was a dominant hypothesis that Alzheimer's is caused by the deposition of unwanted proteins in the brain, amyloid plaques, and tau proteins. And most of the efforts in biotechnology and research for Alzheimer's were to design medicines that could remove those Alzheimer's plaques.

DODI: Joshua and his team studied 33 patients split between, of course a randomized placebo arm and the recipients receiving their investigational therapy.

DR JOSHUA HARE: We really tried to study the mechanism. We measured a whole host of biomarkers in the blood that give us an insight into what the mechanism is. And we did imaging on the brain, we found two things that were very exciting and provocative that will be tested for validity in the phase two study. Some of those things we found provisionally was improvement in anti-inflammatory markers in the bloodstream, but also an improvement in biomarkers for blood vessel function. Very importantly, we also did imaging with MRI of the brain and found provisionally that the size of the hippocampus got bigger in patients who receive the Lomecel-B. The hippocampus is one of the very important sites in the brain where new memories are formed. So, we think that there was a very, very exciting clue that the cells might be actually allowing the hippocampus to grow more neurons and function better. And we look very much forward to testing that in our upcoming phase two study.


CONOR: So, Joshua, quite a lot like Lucy, is not done with the research yet. So, it's super early days. What else are they learning from these very early studies?

DODI: Well, there are several hypotheses for how to treat Alzheimer's. One of them is the hypothesis of neuro inflammation, which is that a major contributor to Alzheimer's could be that the brain is inflamed.

DR JOSHUA HARE: We had a number of supporting information for our hypothesis, one was the fact that the Lomecel-B had the potential to reduce neuro inflammation, and two we had already shown that it improved cognitive function in people with ageing frailty. So, this was made perfect sense for us to go ahead and do our study.

CONOR: So, this is really, really early days. I think it's important to underscore that less we give people false hope, but you know, when does Joshua think there's going to be results?

DODI: At least five or 10 years away?

DR JOSHUA HARE: A big part of that will depend on the results of the phase two. We'll have the results of the phase two within five years and depending how good they are, will help us accelerate the phase three.

CONOR: So, he's made this really important point, right, you know, Alzheimer's Disease International services, and it's estimated 50 million people living with the disease and dementia globally, and a treatment would have this huge impact on global health.

DODI: Exactly. While it is too late for it Sinéad and her mom, the fight against Alzheimer's is slow, and steady, and hopeful.

DR JOSHUA HARE : Well, that's the whole wonderful part of being in the field of discovering new therapy, it's a wonderful endeavor to try to help people who presently have a major unmet need. So, that maybe combined scientific discovery, which is wonderful in and of itself, but it also is coupled to doing some good for people who are suffering and are in need. So, it's a wonderful combination. And those of us who get to work in this field are very fortunate.

CONOR: This is a tough one because it takes an extra-long time. Phase one studies are safety studies. So, we're a long way off anything being proven to work but feels like while it may be too late for many, and maybe even for you and I, Dodi, that things are moving forward.

DODI: What I like about what we learned from Lucy and Joshua is just that open curiosity, you know. A colleague who was looking at another kind of cancer thought maybe here's a connection for you to study about the brain. And, you know, there are several paths to finding a discovery that can help us lead better lives as we age because we want to age. We're lucky if we get to be old, aren't we?

CONOR: Exactly, and ageing gracefully? Well, you know, it's the way. Our executive producer was Andrew Kilin, and this podcast is produced with the help of Bethany Grace Armitt-Brewster. Editing, mixing and music by Tom Henley and Banda Produktions. My name is Conor McKechnie.

DODI: And I'm Dodi Axelson. Please rate us on Spotify, where we've got a poll running under the episode description. You can also find us on whichever platform you use to listen. We'll see you when we come back with another episode of Discovery Matters. Thanks for listening.

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