“Brain cells respond very differently in a 3D versus 2D environment,” says Dr. Nygaard. “With 3D bioprinting, and our other advanced 3D models, we’re essentially trying to replicate how brain cells actually function and interact with one another in the human body.”

Similar to 3D printing, whereby a digital design is built layer upon layer, with a 3D bioprinter, a replica of living human tissues is printed in thin layers using biomaterial.

In the case of Dr. Nygaard’s lab, stems cells, derived from the blood of Alzheimer’s patients, are first reprogrammed into brain cells. Then, using the bioprinter or other tissue engineering methods, three-dimensional tissue models resembling areas of the patient’s brain are generated, including microscopic, ball-like structures known as “neurospheres.”

“Once we understand the root of Alzheimer’s resiliency, we can use that to guide the discovery of new treatments or to repurpose existing drugs that could one day stop — or even reverse the disease.”

– Dr. Brian MacVicar

“These 3D human brain cell models are allowing us to gain greater insights into the basic cellular mechanisms that cause the brain to degenerate in Alzheimer’s,” says Dr. Nygaard.

Already, as part of a pioneering research project with UBC’s Dr. Brian MacVicar, professor of psychiatry and Canada Research Chair in Neuroscience, the 3D neurosphere model has been used to examine the role that oxidative stress (the imbalance of free radicals and antioxidants) plays in the death of brain cells of Alzheimer’s patients.

Using state-of-the-art neuroimaging techniques, Dr. MacVicar, a world leader in neuroinflammation, and his team are able to offer an unparalleled visualization of the cellular processes taking place in infinitesimal spaces, some only 100 micrometres (one millionth of a metre) wide.

So far, using the 3D model, they’ve shown that microglia — the immune cells of the brain — offer protection from the damage caused by oxidative stress triggered by the presence of amyloid.

“Here we can see how the neurons interact with the microglia,” says Dr. MacVicar, pointing to a rotating fluorescent image of a neurosphere. “By studying these individual interactions between the cell types, we can shed new light on how Alzheimer’s starts.”

And, thanks to a close collaboration with UBC’s Dr. Freda Miller, professor in the department of medical genetics and a leading stem-cell expert, the research team has been able to gain even greater insights — isolating single cells to examine genetic factors at play. 

“By looking at gene expression profiles in the individual brain cells, we’re on the path to addressing questions in Alzheimer’s research that would not have been possible only a short time ago,” says Dr. Miller.

That includes addressing the question of Alzheimer’s resiliency.

According to Dr. Miller, who brings a unique perspective to the research collaboration as a developmental neurobiologist studying how stem cells build the brain, resiliency is a particularly important research frontier in Alzheimer’s.

“Traditionally, the world has asked: Why do people get dementia? But we’re flipping that on its head and asking an equally important question: Why do some people not get dementia?”

Could resiliency be the missing link to understanding Alzheimer’s?

While no one knows exactly how many people are actually ‘resilient’ to Alzheimer’s disease, Dr. Nygaard estimates about 20-30 per cent of older adults have similar levels of amyloid in their brains to that of someone with Alzheimer’s, yet exhibit no signs of dementia.

“By studying those who have escaped or delayed developing dementia, our hope is to understand what’s driving that protection,” says Dr. Nygaard.

In the coming years, the team will build on their latest work, generating 3D ‘mini-brains’ of people with Alzheimer’s resiliency — applying the same powerful neuroimaging and genetic analysis techniques.

“Once we understand the cellular and genetic mechanisms at the root of resiliency, the hope is to harness that resilience to guide the discovery of new treatments or even repurpose existing drugs that could one day stop — or even reverse — progression of Alzheimer’s disease,” says Dr. MacVicar.

According to Dr. Nygaard, the time to find new treatments for Alzheimer’s patients is now.

“We still don’t have a treatment that can stop the progression of Alzheimer’s, and that really haunts me. But it also keeps me motivated.”

– Dr. Haakon Nygaard

“As a physician, if your patient gets a bacterial infection, you can give them antibiotics. If your patient breaks their leg, you can fix it. But if your patient is diagnosed with Alzheimer’s, there’s still relatively little we can offer them. There is no cure,” says Dr. Nygaard, who works directly with Alzheimer’s patients and families as a neurologist.

Over the years, Dr. Nygaard has watched his patients being slowly robbed of their identities, memory by memory. And he’s watched families robbed of their loved ones, one day at a time.

“We still don’t have a treatment that can stop the progression of Alzheimer’s, and that really haunts me,” says Dr. Nygaard. “But it also keeps me motivated.”

At the end of the day, it’s the many patients and their families who are the driving force behind Dr. Nygaard’s research — as well of those of his collaborators.

“Imagine if we could give even 10 more good years to people who are in the early stages of Alzheimer’s,” says Dr. Miller, who strongly believes the lessons they learn about Alzheimer’s resiliency could one day be applied to other neurodegenerative diseases, including Parkinson’s.

“The potential of this research is enormous.”