Titans of Science: Tara Spires-Jones
PodcastsThe Naked ScientistsTitans of Science: Tara Spires-JonesUntangling Alzheimer's disease07 July 2026Titans of Science returns with Tara Spires-Jones, a world-leading neurobiology researcher and Director. . .
PodcastsThe Naked ScientistsTitans of Science: Tara Spires-JonesUntangling Alzheimer's disease07 July 2026Titans of Science returns with Tara Spires-Jones, a world-leading neurobiology researcher and Director of the Centre for Discovery Brain Sciences at the University of Edinburgh. She studies the mechanisms and reversibility of neurodegeneration in Alzheimer's disease and other degenerative brain diseases. We explore Tara's path to neuroscience, the history and biology of Alzheimer's, and treatments developed to overcome it. Tara has been speaking with Chris Smith. Tara Spires-Jones: A brief history of Alzheimer's diseaseTara Spires-Jones, University of EdinburghTara Spires-Jones was born on the 8th of April, 1976, in Uvalde, Texas. She attended Leander High School before completing a double honours in Biochemistry and French, at the University of Texas at Austin. In 1999, she flew across the pond to undertake postgraduate studies in Neuroscience at the University of Oxford, before heading back to the US to Massachusetts General Hospital and the Harvard Medical School as a researcher. Tara has lived in the Scottish capital since 2013, and she is now Professor of Neurodegeneration and the Director of the Centre for Discovery Brain Sciences at the University of Edinburgh. Last year, she was appointed co-lead of the Synapses, Circuits, Cognition and Physiology Division at the UK Dementia Research Institute. Tara's research focuses on the mechanisms of neurodegeneration in Alzheimer's disease, as well as other brain disorders and ageing. Her work specifically investigates why nerve cells and the junctions between them, which are called synapses, become dysfunctional and die in these diseases, in the hope of developing effective treatments. Tara was also elected Fellow of the UK National Academy of Medical Sciences in 2024, and is a Fellow of the Royal Society of Edinburgh since 2026, and served as President of the British Neuroscience Association from 2023 to 2025. She's just been awarded the Stuart Pickering Brown Prize for Lifetime Achievement in Dementia Research, and she's been speaking with Chris Smith. . . Chris - Hello Tara. Tara - Hello Chris. Chris - So, neuroscience, what took you down that path?Tara - Yeah, it's a good question. So I grew up in the 1980s in the middle of nowhere Texas, and spent my childhood outside. I don't know if you were also a child of the 80s, but there wasn't internet. And I was fascinated by the natural world and sort of always wanted to be a scientist. And, when I was at university as an undergraduate, I was studying biochemistry, so fascinated by how the inside of cells work. When I got towards the end of my undergraduate degree though, I started thinking about what problems, what sort of questions would I like to ask as a scientist? And what really attracted me was neuroscience because it's kind of our last frontier in biology. We don't really understand how the brain works, how we make all these beautiful things like memory and thoughts and emotion. And so I just kind of steered myself down that direction, and found an amazing mentor and came over to Oxford for grad school. Chris - And how did you end up in the Alzheimer's space?Tara - I started off as a neuroscientist on the other end of the life course actually. So I started off studying neurodevelopment and how the brain uses information from the senses, like sensory information to develop during sort of just after birth. But during my PhD, I ended up changing direction, partly because the question I was asking just didn't work. I was sent as a PhD student to find something that turned out not to exist with a really fancy microscope. [Tara laughs]. So when I got to that point, that's one of the things I'm sure you hear a lot from your guests is that science doesn't work the way you expect, right? So when I got to that point, I had an idea of looking at the plasticity or the ability to change of synaptic connections, not in development like I started out, but in degeneration. And I went into a model of Huntington's disease and was one of the first people to discover changes in synapses in this mouse model of Huntington's. And after studying Huntington's as a grad student, I went to interview in Boston at Mass General and met an amazing scientist named Brad Hyman, who turned out to be my mentor. And he attracted me to Boston, essentially with a microscope that was amazing. And he said, look, synapses we think are really important in Alzheimer's. People aren't really studying them enough. You're an expert on synapses. I have a really cool technique and a microscope you could use to study them. And that's where I started. And that was 2004. So over 20 years ago now. Chris - What was the technique and what were you actually looking at?Tara - Yeah, so the technique is called two photon imaging. What's cool about that is when you pulse a laser and you get two single light particles, photons, to hit something at the same time, you can penetrate pretty deep into brain tissue. So we were able to look through a window into a mouse's brain and follow over time how synapses die around plaques, and plaques are one of the pathologies in Alzheimer's disease. So we were able to see synapse degeneration in the living brain over time. And importantly, we were able to rescue that degeneration with treatments that remove the amyloid from the plaques. And that was one of the really early experiments down the road to some of the first disease modifying treatments. I'm not taking credit for those. It was not my idea to remove plaques in the first place, but I did play a small part in the development of the very first drugs that can slow the progression of Alzheimer's disease. Chris - Let's back up a little tiny bit then and consider the disease as a whole. What actually is Alzheimer's disease and how does that fit into the umbrella term dementia?Tara - Yeah, so Alzheimer's disease is the most common cause of dementia, which is the set of symptoms or the clinical syndrome. Unfortunately, I would imagine all of your listeners are very familiar with what dementia is. It's this idea that you lose cognitive function over time. And in diseases like Alzheimer's, that usually starts with problems with memory, but it progresses to problems with planning and thinking, the ability to look after yourself and live independently. So dementia is the umbrella term for the symptoms, but those symptoms can be caused by lots of different diseases. Alzheimer's is the most common, but there are also diseases like frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease, dementia, etc. A whole host of underlying brain pathologies that can cause those symptoms of loss of cognitive function. Chris - And in Alzheimer's specifically, what happens?Tara - So that's what I've been studying for the last 20 years and what people have been studying as a whole in the field for over 125 years. But we know that over the course of Alzheimer's disease, you have the buildup of two different pathological proteins in the brain. One of them is called amyloid beta and it clumps into what we call plaques. And they are big clumps outside of the cells in the brain. And the other pathology is called neurofibrillary tangles. And those tangles are made of pathological tau protein and tau clumps up inside the neurones of the brain cells in the brain. And this happens over the course of decades. So the plaques build up for at least 20 years before symptom onset. The tangles and where they spread in the brain actually tracks better with the loss of cognitive function. And so the downstream of these two pathologies is the neurones die. So your brain literally dies over the course of decades. And that's why you lose your cognitive function. Chris - Now, when you say this has been studied for over 125 years, would that have been Alzheimer? Because Alois Alzheimer was a doctor, wasn't he? Was he the person that gives his name to this because he studied it?Tara - Yes, he's the most famous. But I'd like to point out that it was a really interesting story why we named it Alzheimer's disease. So the person who first described the plaque pathology was named Oscar Fisher. And he described the plaques, they were actually called Fisher plaques for quite a while. He described those plaques in the very early 1900s. Alzheimer described tangles and plaques, both in the brain of a person who had Alzheimer's type dementia, or what we now call Alzheimer's dementia. And then after Alzheimer, there was a black neuropsychiatrist called Solomon Carter Fuller, who, who really progressed the field, translated Alzheimer's work from German into English. And the reason it's called Alzheimer's disease is because Alzheimer's mentor, who was named Emil Krappeland, he was a really famous psychiatrist in Germany. And he was directly competing with a really famous psychiatrist in Prague called Pick, whose Pick disease is named after. And when Krappeland, who was Alzheimer's boss essentially, saw his case study, he described this one person's brain. And then Krappeland wrote that as a case study into his huge textbook of psychiatry that was the biggest in the world at the time. And in that textbook, he named it Alzheimer's disease, I think as part of a competition with Pick and, and because Pick was Oscar Fisher's mentor. And one of the reasons I think Fisher disease is not what we call it is because Fisher was actually killed by the Nazis in the 1940s. Tara Spires-Jones: The biology of Alzheimer's diseaseTara Spires-Jones, University of EdinburghTara Spires-Jones kicks off our latest series of Titans of Science. She has been telling Chris Smith about the biology of Alzheimer's disease, and what we have learned from the early pioneers. . . Chris - They were looking down a microscope and seeing very similar things to what you see today when you look down a microscope, but they wouldn't have had the molecular insights that we have today. Tara - Yeah, exactly. So at the time in the early 1900s, there's just been this technological boom in microscopy, right? So now we had compound microscopy, and another technological advance in how you can fix tissue so that it can be stained and advances in staining the tissue so you could visualise things. Fisher and Alzheimer were able to look down the microscope and see these pathologies, plaques and tangles that we still see today. Like you say, they didn't know what they were made of. And that took until the 1980s, when the sort of molecular revolution came about to understand what proteins are involved. But yes, they were looking down a microscope just like I do today, although mine are more expensive and fancier. [Tara laughs]. Chris - But there are two things going on then. There are things that go wrong inside cells and things that build up outside cells. Are they one and the same? Does one cause the other? Does, do they occur in parallel? Do we actually know how the two are related?Tara - There's still some debate about that. So the predominant hypothesis in the Alzheimer's field about how the disease works is called the amyloid cascade hypothesis. And this was put forward by, one of the scientist's is John Hardy, Sir John Hardy, who's a professor at UCL. And what he did is he discovered that mutations in families that have familial Alzheimer's disease, they cause increases in the amyloid protein that clumps and plaques. And downstream of that, and it must be downstream of that because there's a single mutation in the single gene that encodes amyloid beta, called the amyloid precursor protein. And those people who have mutations, these familial Alzheimer's mutations, go on to develop tangles, and then cell death, and Alzheimer's disease. So that's proof that at least in the familial form, which is very rare, it's about 1% of people with Alzheimer's have a genetically inherited dominant form. But in that rare condition, it is very clear that amyloid is upstream and that somehow, and we still don't fully understand how, causes the downstream tau pathology, neurodegeneration, and the big brain inflammation that we see, the sort of gliosis that we see in the brain. In sporadic Alzheimer's, which is the vast majority of cases, there's people who don't have a gene that directly causes the disease, but might have genes that increase their risk and lifestyle factors that increase their risk. There's still some debate about whether amyloid is the driving factor, but most of us in the field agree that amyloid is upstream in the process. But there are still a lot of mysteries about how that leads downstream to the tau pathology and the neurodegeneration that actually are associated with symptoms. Chris - Don't people who have Down syndrome develop Alzheimer's changes much sooner? Because the gene for beta amyloid is on the chromosome they have an extra copy of, chromosome 21. Tara - Exactly. So when you have an extra copy of chromosome 21, you have an extra copy of the amyloid precursor protein, and that's sufficient to drive more production of this amyloid and Alzheimer's disease in people with Down syndrome. And it's a similar mechanism to some of the mutations. Even if you don't have three copies, the mutations all either increase the production or increase the stickiness or the propensity to aggregate of the amyloid beta into those plaques. Chris - Why should though, just making a bit more of something that your brain clearly needs, because all of us have this gene, we've all got it turned on in our brains anyway, this beta amyloid gene, why should extra amounts of it then turn into a disease process? And what does the gene even do?Tara - For the first question, why does this cause a disease? We really don't fully understand. What the gene does normally is pretty well understood, although not fully. So amyloid precursor protein, which is the parent protein of the amyloid beta, is involved in neurodevelopment. It's involved in repair. If you get some damage to your neurone, this APP goes out and tries to fix it. So that's important. But this cleavage product, this A beta, when it gets released from the neurones, because it gets caught in the membrane and then it gets spit out of the cell, and when it's released, normally it should be cleared from the brain. Like your brain has, just like any cell, has turnover of its proteins. You make stuff, it's used, and then it's either degraded or cleared. And in people with Alzheimer's, we think, and it's not fully understood, we think that there's some deficit in clearing the amyloid from the brain that causes it to clump up. And we know that small clumps of amyloid, not the massive plaques, but small oligomers, so a few copies of this A beta stuck together, are very toxic to synapses, my favourite part of the brain. So when amyloid beta is one of the things we discovered years ago now, is amyloid beta sticks to synapses and that we think is directly causing the synapse death. And when the synapse dies, your cells can't talk to each other properly anymore and you start to have that cognitive decline. Chris - How does that link though, to these tangles building up inside the cells? Is it the injurious effect of the toxic forms of amyloid poisoning your synapses in the way you say, that then causes some kind of cascade into the cell, and that then causes the things that are inside the cell, the tau proteins, to tangle up?Tara - This is where the mystery comes in. We still don't fully understand this. There are lots of good experiments that hint at various mechanisms linking A beta to tau. One that I think is particularly interesting is we think that amyloid plaque pathology and A beta are probably gating the spread of tau pathology out of a small part of the brain. Most of us, as we age, have a tiny bit of tangles or tau pathology just tucked right in the medial temporal lobe in a very small part of the brain called the transentorinal cortex and parts of the brainstem. And if you keep it there, in that part of your brain, it doesn't affect your function. But if the tau gets out, if somebody opens the gate and the tau starts to spread through the brain, then you start to have symptoms. And it's when the amyloid pathology gets down towards that part of the brain that you start to see the tau spreading. And in model systems, when you combine little bits of tau in one little part of the brain with amyloid plaques, it accelerates the tau spread. So that's one of the things it's doing, but there are lots of things that we don't fully understand about how amyloid links to tau. One of the things that's probably happening is amyloid causes a huge amount of inflammation around the plaques. Those changes in the immune cells in the brain, we think are causing damage to the neurones, and they're probably linked somehow to the tau pathology, but we don't really fully understand. Chris - And can it spread through the brain or do you produce these inflammatory proteins all over the brain and they build up all over the brain? And therefore, if you look anywhere in the brain, you will find these plaques of Alzheimer's disease?Tara - Both plaques and tangles do spread through the brain. Plaques begin out in the neocortex, the part sort of on the top of your brain, the beautiful, curvy sort of gyrations that we all think of when we think of a brain. The amyloid starts out in what we call the default mode network. So that's parts of the brain that are active when you're just sort of doing nothing, when you're just sitting and thinking. And then it sort of spreads down through the rest of the brain. The tau, like I mentioned, starts in a very tiny part of the medial temporal lobe and then spreads through neural circuits. So it goes, jumps out of one cell, we think, and we've got some evidence to show this in animals and we've got some really circumstantial, but I think convincing evidence that this is happening in human brain as well. So tau starts in one cell, it travels down to, down the axon to the synapse. So the axon is the sort of the wire that sends the signal. It jumps out of the presynapse and it jumps into the next cell and that synapse is along the side that, so into the postsynapse of the next cell in a whole different brain region. Because your neurones, one of the remarkable things about the brain is your neurones have these hugely long processes. The axons from your motor cortex can go all the way down to the bottom of your spinal cord, can be a metre long. So the cell body is up in your brain and the synapse is down in your spinal cord. And within the brain, this happens on a smaller scale. So from that transenterinal cortex, there are axons that go into the hippocampus, which is a really key brain area for memory. And that's one of the reasons that memory is one of the first symptoms in many people with Alzheimer's, is because that circuit from the entorhinal cortex to the hippocampus is hard hit by tau pathology very early on. Chris - Is this also why people, and you've alluded to it here, people will presumably have this disease for a long period of time before they're symptomatic with the disease. And is that because they're basically accruing damage that's building up in the cells, but it hasn't yet spread and begun to claim other territories in the brain that will then affect brain function significantly until you get to a threshold point?Tara - Yeah, partly because your brain is absolutely amazing. We've got this ability of the brain to, we call it plasticity in neuroscience, the brain to just make up for damage or resilience, we also call it. So you're building up plaques in the brain for at least 20 years before you have a diagnosis of Alzheimer's disease, but your brain can just put up with a bit of plaques. When you then have the tau pathology that spreads through the brain and starts to kill the cells, once enough cells have died, your brain cannot make up for it anymore by making new synapses and sort of making the rest of the network make up for it. And very interestingly, that amount of that set point of the time when you will have symptoms really varies based on your lifestyle and your background. So people with really high levels of education have built these big, robust brain networks, and they can put up with a lot of pathology in their brains before they have symptoms. And that's something we call cognitive reserve. And that's why I spend a lot of time doing public engagement events, because I want to tell people that it's not to blame people who have dementias, but there are things that we can do as individuals to boost our own brain resilience. It won't work forever, but we can make our brain networks really robust and reduce our chances of developing dementia or delay the onset because we've given our brain the best chance to put up with any pathology that's building up.