Genetic mutations are offering new insights into Alzheimer’s disease

Rare genetic mutations that cause early-onset Alzheimer’s disease are helping scientists at the University of Toronto uncover mechanisms involved in the disease, which may lead to new diagnostic tools and therapies.

“This research has been crucial to understand more about what is happening in the Alzheimer brain. When you have a mutation that results in degeneration, you can see much more clearly how a single molecular alteration can lead to disease,” says Martin Ingelsson, a researcher at U of T’s Tanz Centre for Research in Neurodegenerative Diseases, who moved from Sweden to Toronto in 2021.

“We can then apply some of these findings to explain how Alzheimer’s disease is initiated and progresses over time in the vast majority of patients who are considered sporadic, that is, they do not have a single genetic mutation.”

Genetic research is one approach to learning about Alzheimer’s disease and its effects on the brain more broadly.

For example, Lars Lannfelt, Ingelsson’s former supervisor at the University of Uppsala in Sweden, discovered the “Arctic mutation,” which causes a particularly toxic form of amyloid beta protein called protofibrils. This research ultimately led to the development of lecanemab, a form of immunotherapy for Alzheimer’s disease that is approved in the United States and currently under review by Health Canada.

In 2021, Ingelsson and his colleagues in Uppsala, notably Dag Sehlin and PhD candidate María Pagnon de la Vega, described the “Uppsala mutation” and examined how it causes disease. The team identified this mutation in a family with members who were diagnosed with Alzheimer’s disease in their early 40s and rapidly deteriorated.

Their analyses, published in Science Translational Medicine, suggested that the mutation accelerates the formation of amyloid beta fibrils that build up into the plaques that are characteristic of the Alzheimer brain, enforcing the importance of amyloid beta in the disease development.

“This deletion speeds up the aggregation of amyloid beta so that it forms fibrils very rapidly. It both promotes an enzyme that cleaves out amyloid beta from its precursor protein and slows a protective pathway that prevents it from being formed, leading to overall higher levels of amyloid beta” says Ingelsson, who is also a senior scientist at the Krembil Research Institute and clinician-scientist at Toronto Western Hospital, University Health Network.

“It was the first time that we could demonstrate not only one, but actually up to three effects that were leading to disease in people with an early-onset Alzheimer’s disease mutation,” Ingelsson says.

Building on that work, Ingelsson and the Swedish researchers recently developed an animal model with the mutation. They used various types of analyses to understand more about how the mutation causes disease and the effects it has on the brain. Their findings were recently published in Acta Neuropathologica Communications.

Of particular note, they found that the amyloid plaques caused by the Uppsala mutation do not generate inflammatory reactions around them, unlike what is seen in other forms of Alzheimer’s disease — although the implication of that is not yet clear.

“This is a completely new observation, and we think it is important to keep studying it to better understand the relationship between Alzheimer’s disease pathology and inflammation,” Ingelsson says.

Ingelsson’s research at the Tanz Centre is also examining new approaches to treat Alzheimer’s disease and Parkinson’s disease, such as immunotherapy and gene therapy, as well as early-stage work using skin biopsies to detect Parkinson’s disease and related disorders. Ingelsson says that his clinical work has a heavy influence on his research program.

“Each side influences the other in a way that keeps my interest at the highest level,” he says. “Working with patients give me a good holistic perspective on neurogenerative diseases and their impact, and it also helps me to better understand what research in the lab has the potential to make a difference in the clinic.”