By Kelly Haggart
The Gazette recently chatted by phone with Graham Collingridge, guest speaker at the Alex Trebek Forum for Dialogue on May 4, 2017, when he will talk about how we store memories and how our ability to learn and remember becomes impaired in Alzheimer’s disease. The award-winning neuroscientist, who moved from the UK in 2015 to chair the Department of Physiology at the University of Toronto, is also a senior investigator at the Lunenfeld–Tanenbaum Research Institute at Mount Sinai Hospital. In 2016, Collingridge and two others won the prestigious Brain Prize for research that helps explain what’s going on at the molecular level in learning and memory. This work helped with the development of memantine, one of only two treatments currently available for moderate to severe Alzheimer’s disease.
What are our chances of developing dementia?
Even with lifestyle changes and the best health care in the world, roughly one in three people over the age of 85 will have developed Alzheimer’s disease or a related dementia — that’s a very scary number. Currently more than half a million Canadians have dementia. Society is ageing, and the biggest risk factor for Alzheimer’s is ageing. That said, the incidence has recently been shown to be decreasing in highly educated populations in the US that take care of their health and have access to high-quality healthcare. But on the whole, it’s a huge health concern, particularly in Indigenous populations, and is partly a socio-economic issue.
What goes wrong in the brain of a person with Alzheimer’s?
Our memories are stored at our synapses, the vital connections between nerve cells in the brain. We form synapses throughout our lives, though most develop during the first three years of life. For a while, we have far more connections than we need, and the ones that aren’t required are pruned.
We believe the physiological process that enables the pruning of synapses goes awry in Alzheimer’s disease. It gets overactive — a bit like aggressive pruning, where the roses get chopped off as well as the branches you wanted to get rid of. The more you exercise your brain and form synapses in the first place, the better your chances of warding off conditions like Alzheimer’s that remove these synaptic connections as you get older.
What is the role of the protein you identified in your research?
I was working as a post-doc at the University of British Columbia when I identified the role of a protein on the synapses that is known as the NMDA receptor. Research by one of my Brain Prize co-recipients later confirmed that if you prevent the activation of this protein, you prevent learning and memory. When I was working on this 35 years ago in Vancouver, I had no idea how relevant the NMDA receptor would be for understanding disease and developing therapies for Alzheimer’s, autism, schizophrenia, depression and many other major brain disorders. But it has now become clear that understanding this process is at the heart of understanding what goes wrong in these conditions.
Are there promising treatments on the horizon?
Trillions of dollars have been spent to develop new therapies for Alzheimer’s, but only one has made it into clinics in the past 10 years. Memantine, which targets the NMDA receptor and normalizes the pruning process, delays cognitive decline by months. But if we can delay it by years, then people will live with normal cognition until they’re 100 and probably die of something else.
If we get a better fundamental understanding of the disease, we will get better drugs. You can understand why governments want the medicines tomorrow, but unless you’ve done the basic research to understand the science, you’re going to waste your time. One hopes there will be a shift back to a balance between government support for discovery science and developing the medicines, which is best done by academics in collaboration with industry.
Are factors in our modern lives triggering brain disorders?
Chronic stress, for one, almost certainly contributes to the prevalence of diseases such as Alzheimer’s, and society is increasingly in a state of stress. You only have to look at the student population — one in three graduate students seems to be suffering some mental health disorder, usually stress-induced.
Substance abuse, be it alcohol or marijuana, is associated with chronic stress and in principle could be making the situation worse. We know that chronic alcohol use can lead to memory deficits and loss of neurons and synaptic connections. Who knows what the long-term consequences of the pending legislation on marijuana are going to be? We’re not going to know the results of that experiment until we assess the elderly population in 20 or 30 years.
What technologies are helping to advance the field?
To understand what can go wrong in diseases such as Alzheimer’s, we need to know how the proteins that are critical to brain function work normally. To do this, we really need to be able to visualize them, to see them moving in real time. This is now technically possible using advanced microscopy and the so-called optogenetic approaches, which are fairly new. Technology is also going to improve health care provision enormously. In a number of years, one can imagine robots assisting elderly patients with dementia.
To make important advances in understanding requires applying different technologies, and no one person alone is qualified to do that. Scientists become extremely focused — I define myself as an expert in a very tiny area. But to make breakthroughs, you have to apply a highly multidisciplinary approach, so collaboration is increasingly the way forward. I’ve been in Canada only 18 months, so I’m just starting to know who’s working in the various places. But I do know Stephen Ferguson at uOttawa’s Brain and Mind Research Institute, who is doing extremely important work on Alzheimer’s disease and is the sort of scientist I’m likely to collaborate with in the future.