Blog – How Dogs Are Helping Us Understand And Solve

Upon hearing that dogs can get dementia, people, naturally, often get really sad. No one wants to think of our best furry friends experiencing the memory less, confusion, and functional decline that we associate with the human disease. Let me reassure you that this story has a good ending.

One of the big problems in dementia research is that it’s really hard to study the actual biology of the disease: you can’t go looking into the brains of people with dementia very easily, and we can’t see the earliest stages of what happens in the brain – often decades before symptoms develop – at all. This has forced us to use rodent models to better understand the biology of dementia and test potential therapies on. But rats and mice don’t get dementia naturally, have different brains and immune systems to us, and age much faster. While they have their uses in carefully controlled experiments, the many drugs tested in the limited rodent models haven’t translated well to human use. We need better models.

Here’s where dogs, as usual, come the rescue. Unlike rodents, around 14% of dogs naturally develop an age-related dementia syndrome (known as canine cognitive dysfunction) that strikingly resembles dementia caused by Alzheimer’s disease. They develop progressive memory loss, disorientation and confusion, and can become anxious or aggressive as they stop recognising familiar people and animals. They can get stuck behind furniture, stop understanding how doors work, pace in circles, and forget how to get outside in time to do their business. Eventually, they stop enjoying playing, lose interest in food, and the gradual functional decline is fatal in the end. (In case you were wondering, this can happen to all dog breeds, but it’s more common in smaller breeds who live longer).

The key difference here is that unlike rodents, where dementia is induced by genetic manipulation, in the dogs, it’s natural (i.e. sporadic), and likely matches the complexities of the human disease much better. Genetically, the canine genome has near exact or exact homology for key Alzheimer’s genes such as APP, MAPT, and ApoE, and anatomically, dogs have brains that are much more similar to ours too. Their hippocampus, a brain region seriously affected by Alzheimer’s disease, is much closer to the human version than that of the rodent, and 10,000 years of co-evolution has developed a profound level of emotional, linguistic, and social cognition in dogs relevant to humans. Moreover, pet dogs share an environment with us. They drink our water (and eat our food), are exposed to the same air quality and environmental pollutants, often exercise alongside us, have social lives, and can even go to school. They’re exposed to the same pathogens and infections as us and have similar experiences of diseases like diabetes and heart disease, which are thought to be important for Alzheimer’s risk. Given how crucial we think social and environmental factors are in the development of dementia syndromes, this gives dogs a leg up on even other lab animals who are more similar to us like non-human primates. Dogs also have larger brains without being inconvenient, live longer while still be able to do tractable research, and are easy (and more fun) when it comes to behavioural testing.

Is it old age or is it dementia? Older dogs can suffer from dementia, also known as canine cognitive dysfunction syndrome. It’s thought to affect nearly a third of 11 to 12-year-old dogs and over two-thirds of dogs aged 15 to 16 years.

So, dogs have a similar pattern of cognitive decline to us, share an environment and complex neuroanatomy, and have coevolved with us for many millennia. What does the pathology of the disease actually look like in their brains though? Intriguingly, these dogs also develop amyloid plaques and hyperphosphorylated tau accumulations, just like in the human disease. While these hallmark pathologies in the dogs typically reflect a much earlier stage of disease, what’s particularly interesting is that the pattern of brain regions affected, often referred to as Braak staging or regional vulnerability, which is so stereotyped in humans, is also reflected in the dogs. Dogs also experience age related brain iron accumulation in the same regions as humans, another suspected disease pathway, and seem to have signs of neurodegeneration too. In this way, dogs could possibly give us insight into the earlier stages of disease formation that are harder to access in humans.

So our dogs, who reflect our biology and disease risk in many important ways, also seem to develop an Alzheimer’s-like dementia syndrome that is similar to ours.

When does the good news start? Let me transition to the good news with stories of two projects from around the world working with the dog model.

The first is in Australia, from the Regenerative Neuroscience Group in Sydney, whom I was lucky enough to work with a few years ago. Under the leadership of Professor Michael Valenzuela and Dr. Tom Duncan, the small group did a lot of work to try and characterise canine dementia and develop a stem cell replacement therapy to try and treat it. Don’t worry – the whole point is that they’re community pet dogs, not housed as lab animals! They’re treated just as if they were human patients. As the therapy was highly experimental, most dogs were on the verge of being put down before undergoing a surgery to inject some of their own stem cells into their hippocampus.

In what was a very small and early-stage trial, almost all of the dogs experienced an improvement in their dementia, and some had a full remission and lived on for several more years. Leo, one of the dogs, has a particular stand out story. Leo had used to work as a therapy dog in an aged care home, but as his dementia progressed and he became increasingly anxious and aggressive, he had to stop work, and would even lash out at family members. After his stem cell treatment, not only did his dementia disappear, but he was able to live for over two more years dementia free and go back to work as a therapy dog, before eventually passing of unrelated causes. This, as you might imagine, was extremely exciting. A small trial and preliminary data, for sure, but proof of principle that in a natural syndrome similar to our own, dementia symptoms can be stopped and reversed for significant periods of time, and the group has now been spun out into the company Skin2Neuron, where they are developing humanised versions of the therapy.

A second project working with dogs is located across the USA, known as the Dog Aging Project. Led by Professor Matt Kaeberlein and based out of the University of Washington in Seattle, the dog aging project has recruited around 45,000 pet dogs from across America into their huge pack, with the goal of following the animals longitudinally across their lifespans to better understand aging itself, as well as age associated diseases like dementia. They collect all kinds of data from environmental and health data to vet records and in some subsets of the pack, genetic testing, cognitive testing, behavioural data, and more. They even have a group being studied as canine ‘centenarians’ – dogs who live much longer and healthier than would be expected for their body size.

It’s still relatively early days for the project, which means that if you’re based in the USA and have a dog, you can and should absolutely apply to get your dog in the study. Another excellent aspect of the project is that they make all their data available to researchers upon a fairly straight forward application, so even if you’re not US based, if you’re interested, you can get involved. Also encompassed in the project is a specific study looking at brain health in aging dogs (where notably they found that ‘not active’ dogs were more than six times more likely to develop dementia), and a trial of the drug rapamycin (TRIAD – Trial of Rapamycin in Aging Dogs). Rapamycin is known to help boost the waste protein clearance pathway called autophagy, which is thought to be important in neurodegeneration and aging more broadly, and that trial is also currently recruiting.

Overall, pet dogs present an interesting and exciting avenue for new research in the dementia field. They make a compelling new model, with overwhelming parallels to humans, advantages over other model animals, and provide an opportunity to engage more of the public with research in a fun and accessible way. With exciting research with dogs happening all over the world, it’s definitely an area to watch (or get involved in), and maybe one of our best animal friends will help us solve one of our greatest challenges.

Ajantha Abey

Author

Ajantha Abey is a PhD student in the Kavli Institute at University of Oxford. He is interested in the cellular mechanisms of Alzheimer’s, Parkinson’s, and other diseases of the ageing brain. Previously, having previoulsy explored neuropathology in dogs with dementia and potential stem cell replacement therapies. He now uses induced pluripotent stem cell derived neurons to try and model selective neuronal vulnerability: the phenomenon where some cells die but others remain resilient to neurodegenerative diseases.

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