Mayo Clinic researchers explore how Alzheimer's disease targets memory-related brain networks

Alzheimer's disease relentlessly targets large-scale brain networks that support the formation of new memories. However, it remains a mystery as to why the disease selectively targets memory-related brain networks and how this relates to misfolded proteins seen by pathologists at autopsy. In an effort to bridge the divide between the targeted memory systems and the misfolded proteins and dying cells underneath, Mayo Clinic researchers have turned to the field of complex systems — an emerging field of science that studies how parts of systems give rise to collective behaviors and how the system interacts with its environment.

In a study of 128 participants in the Alzheimer's Disease Neuroimaging Initiative, which is published in the February issue of the journal Brain, the team of researchers led by Mayo Clinic neurologist David Jones, M.D., proposed a disease model as a pathologic interaction within a complex system composed of large-scale brain networks and small-scale molecules. They looked into the activity of the default mode network or DMN (a brain system known for being active when we perform tasks involving memory or when invoking mental constructs), and related this activity to measures of Alzheimer's proteins. Building on their previous work on DMN activity, the team found that a failure that starts in this system cascades through the brain via increases in activity. These increases in activity traditionally have been understood as a compensatory process; however, this new study suggests that they also may be propagating the disease process throughout brain systems — just like rerouting of power surges can cause blackouts in a power grid.

"We found that this load-shifting process itself may be a major culprit for the development of the Alzheimer's disease," says Dr. Jones, the study's lead investigator and author. "It is not unlike a cascading failure of a power grid. When a hub goes down, other areas of the network are forced to compensate. If the burden shift is too high, it blows off the circuits, and the power is down. This type of failure in our large brain networks may be responsible for the development of the Alzheimer's disease."

These findings, Dr. Jones believes, support a system model that would open up new avenues of preventive therapeutic interventions targeting large-scale brain activity in the years or even decades before symptoms. "This would be akin to cardiologists encouraging the lowering of blood pressure decades before plaques ever develop in the arteries in the heart," Dr. Jones says.