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It’s a pain that many families know all too well: seeing a loved one slowly disappear, day by day, until they are almost unrecognizable; watching helplessly as they lose control of their body and brain. This is the heartbreaking reality for people living with neurodegenerative diseases such as progressive multiple sclerosis, Parkinson’s disease, Alzheimer’s and other dementias – a reality that a growing number of Canadians will face over the next 10 to 20 years.
By 2030, researchers project that nearly one million people in Canada will be living with dementia. By 2050, that number is expected to reach 1.7 million.
Amid these staggering projections, there are still many unknowns about neurodegenerative diseases and memory loss, but within the walls of University Health Network’s (UHN’s) Krembil Brain Institute, progress is taking shape.
Pushing the boundaries of research
The Krembil Brain Institute at UHN’s Toronto Western Hospital is home to one of the world’s largest and most comprehensive teams of physicians and scientists working together to prevent and confront diseases of the brain and spine. More patients living with neurological conditions are treated there than anywhere else in the country.
As Canada’s largest research and teaching hospital, the Krembil Brain Institute is known for pushing the boundaries of research and innovation, with a commitment to develop new and more effective treatments. The goal is not only to improve quality of life for people living with these diseases, but to eradicate these diseases altogether.
A major area of focus for UHN’s Krembil Brain Institute is neurodegeneration and memory loss. Dr. Valeria Ramaglia, one of Krembil Brain Institute’s newest scientists and an assistant professor of immunology at the University of Toronto, is among the researchers pushing this work to new levels. Her work explores the role of the immune system in brain health and disease, particularly in multiple sclerosis (MS).
Multiple sclerosis as a window into memory loss
“Canada has one of the highest rates of MS in the world,” says Dr. Ramaglia. “This disease brings on a wide range of symptoms that often worsen with age. The result is what we call progressive MS, and one of its most devastating consequences is memory loss. There is no fix for memory loss in progressive MS. That is what we are looking to solve.”
Through studying brains donated to research by people with progressive MS, Dr. Ramaglia and others in the field made a groundbreaking discovery: clusters of immune cells sitting at the border of the brain.
“These clusters should not be there,” says Dr. Ramaglia. “We have to ask ourselves: what are these cells and what are they doing?”
By using new tools that let them look closely at how brain cells behave, her team found that these immune cells produce important immune proteins called “complement.”
“In simple terms, complement is a group of proteins, mainly produced by the liver and released in the blood, that help your immune system fight infection,” explains Dr. Ramaglia.
“But in MS, complement is produced at the brain border, and it is linked to damage in memory-critical regions like the hippocampus.”
Studies in pre-clinical models in her lab suggest that complement is not only linked to the damage but causes it.
Earlier work from Dr. Ramaglia on the role of the complement system in nerve trauma led to a patent and the founding of a pharmaceutical company that develops complement inhibitors to treat neuroinflammation and neurodegeneration. Now, the aim is to test whether drugs that target complement at the brain border can help protect the brain’s memory centres. This approach has also inspired a new line of research in the Ramaglia lab that extends beyond progressive MS to other age-related diseases of the brain that impact memory.
If complement contributes to memory loss in progressive MS, could the same mechanism be occurring in other neurodegenerative diseases, such as Alzheimer’s?
Dr. Ramaglia’s motivation to find these answers is also personal. During her studies, her father was diagnosed with Alzheimer’s disease. “I know firsthand what it means to see a loved one fade,” she says. “I share the urgency to find a solution, and I have made it my mission.”
Connecting these findings to Alzheimer’s
Dr. Ramaglia’s research aligns with a groundbreaking theory proposed by UHN senior scientist Dr. Donald Weaver, who has suggested that Alzheimer’s disease may function as an autoimmune disorder – an idea that challenges decades of conventional thinking.
For decades, scientists have focused on beta‑amyloid, believing it to be an abnormal protein that builds up in the brain and damages cells, contributing to Alzheimer’s disease. Dr. Weaver offers a different view, that beta‑amyloid may actually be a normal part of the brain’s immune response, helping to repair tissue and fight infection.
Looking at how the immune system interacts with nerve cells is where the new answers may be found.
— Dr. Valeria Ramaglia, Krembil Brain institute
According to this theory, Alzheimer’s begins when beta‑amyloid can no longer distinguish between invading bacteria and the brain’s own cells, leading it to mistakenly attack the very brain cells it is supposed to be protecting – an immune system misfire.
If Alzheimer’s involves immune‑driven damage, then complement proteins at the brain’s borders may be key players.
Dr. Ramaglia’s work is helping to determine whether the same harmful complement activity seen in progressive MS is also present in Alzheimer’s disease, and whether blocking that activity could protect the brain.
A pathway toward new treatments
Now that scientists have unraveled this first set of clues in understanding the immune system’s role in memory loss, the next challenge lies in identifying when, where and how these immune pathways are activated.
“We need to understand exactly when and where complement becomes harmful and by which mechanism,” says Dr. Ramaglia. “Only then can we design brain-penetrant drugs that reach the right targets at the right time.”
It is also essential to recognize that not all patients develop neurodegenerative diseases in the same way. An additional challenge, therefore, is identifying which individuals are most likely to benefit from immune-targeted therapies. The Ramaglia lab is working to discover biomarkers – measurable signals in blood or spinal fluid – that can help match the right treatment to the right patient, paving the way toward more personalized and effective therapies in the future.
UHN’s Krembil Brain Institute is uniquely positioned for this work. With access to patient spinal fluid and advanced imaging, the team can study complement activity directly in people living with Alzheimer’s and other neurodegenerative diseases, an essential step toward developing clinical trials.
There’s no cure without research
To move this research forward, funding is urgently needed for pre‑clinical studies that test when, where and how complement drives disease. These early studies will build the scientific rationale for complement‑targeting therapies to advance into human trials.
“Research is our greatest opportunity to understand these diseases,” says Dr. Ramaglia. “At the Krembil Brain Institute, we are widening the breadth of our research and asking new questions. What if diseases of the brain where we initially thought that the immune system was not involved are in fact driven by immune mechanisms? Looking at how the immune system interacts with nerve cells is where the new answers may be found.”
For the first time in a long time, those answers feel within reach.
To learn more about how UHN is leading the way in brain care, visit UHNfoundation.ca/health
This article originally appeared in The Globe and Mail, read it here.
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