Shifting paradigms, informing solutions in Alzheimer’s disease

By Alison Palmer, Evaluation and Special Projects Lead 

In 2016, Yasser Iturria-Medina, Ph.D., and his post-doctoral supervisor at the time, Alan Evans, Ph.D., published findings that quietly helped shift how scientists think about Alzheimer’s disease. Today, that work has informed several therapeutic patents and opened the door to a distinct class of drug targets currently being tested on patients around the world. 

The shift 

Ten years ago, the Alzheimer’s disease research field was dominated by a single paradigm – the amyloid-beta hypothesis. Most studies focused on one type of data at a time, such as a specific kind of brain scan.

With the support of Brain Canada, Prof. Iturria-Medina was able to go beyond that one-cause, one-pathway thinking. He and his colleagues brought together multiple biological “layers” at once: vascular changes, protein pathology, structural and functional brain imaging, and more. Using computational, data-driven methods rather than hand-drawn cartoon models, the team showed that these biological factors don’t act in isolation – they interact, propagate across brain networks, and shape disease progression together.

“Our paper confirmed that we need to consider a multi-dimensional view of these very complex disorders, rather than adopting a one-size-fits-all approach.” – Prof. Yasser Iturria-Medina 

For the research community, this finding was significant. For the first time, all those who were trying to challenge the existing paradigm in Alzheimer’s disease research had evidence that alternative hypotheses were worth exploring. “They saw the findings as long-awaited support for their alternative hypotheses,” Prof. Iturria-Medina recounts. 

The early and important role of the vascular system

 
One of the most important findings Prof. Iturria-Medina’s work was the central role of the vascular system in Alzheimer’s disease. The team showed that vascular changes appear early and persist across all stages of the disease, which contrasted with the dominant narrative featuring amyloid-beta at the center of the story. This gave lines of research on blood vessels, inflammation, and blood–brain barrier integrity a powerful piece of large-scale, quantitative support.  

“Even if the amyloid and tau hypothesis were totally true, we know that the clearance of these molecules depends on the integrity of the vascular system,” says Prof. Iturria-Medina. “And once the blood–brain barrier permeability is affected, more agents which could be toxic or negative could enter the brain. That opens a Pandora’s box… it can basically erase everything.”

What’s the impact 

From a solutions standpoint, the 2016 paper is directly cited in several new, therapeutic patents that focus on improving blood flow and repairing the neurovascular system, technologies that drive better brain health and neurorehabilitation. It’s also indirectly implicated in three distinct clinical trials currently underway to target the brain’s blood vessels to assess whether better vascular health can support memory and thinking in Alzheimer’s disease. 

Scientifically, Prof. Iturria-Medina’s work has helped move the Alzheimer’s disease research field toward causal frameworks, looking deeply at the molecular level to better understand how different biological factors drive disease progression over time. It also strengthened the idea that there is not “one Alzheimer’s,” but multiple trajectories and subtypes, each with its own mechanisms and biomarkers.

For Prof. Iturria-Medina, now an Associate Professor at McGill University and researcher at The Neuro (Montreal Neurological Institute-Hospital), this paper became a turning point in his career. It solidified his commitment to a multi-factorial, causal, and personalized view of neurodegenerative disease—one that he now extends to studies on Parkinson’s, ALS, and other disorders. For example, his subsequent work, funded via a Future Leaders in Canadian Brain Research grant, uses large-scale imaging, genetics, blood-based molecular data, and high-resolution single-cell analyses to identify individual “signatures” of disease and to predict who is most likely to respond to specific treatments. Prof. Iturria-Medina feeds these computational insights directly to collaborators who test targeted interventions in the lab, integrating lifestyle factors and social determinants of health for a wholistic approach to prevention and treatment. 

“We’re working with biological data that reflects what is happening at the genetic level, at the epigenetic level, at the proteomic level, so we’re able to simulate how a clinical intervention will affect the brain of every person. We’re even able to help select the right patients or participants for upcoming clinical trials,” he says.

“In reality, everything is connected, so we are trying to connect the most points possible to get the most representative models and estimations to help patients.” 

This is the power of the One Brain approach championed by Brain Canada – by looking at the brain as an interconnected system, Prof. Iturria-Medina and colleagues showed that Alzheimer’s disease is not the story of one molecule, but of many interacting biological factors. This broader view has helped to open new paths of inquiry, towards more precise, effective, and individualized care.