Scaling the Divide in Alzheimer’s Disease: An Integrated Molecular, Cellular and Network-Level Study

Long before memory and other cognitive functions deteriorate in Alzheimer’s disease (AD), subtle changes occur at multiple scales in the brain, ranging from the level of individual molecules and cells to the broader networks that these cells form. How changes across these scales interact and impact one another remains largely unknown. Our main goal thus is to unravel the interrelationship between these seemingly disconnected scales to gain an integrated understanding of disease processes in early AD. Using cutting-edge recording tools, we first aim to capture a real-time, large-scale view of brain activity in AD models. This will allow us to discern how AD pathology, i.e., abnormal deposition of amyloid beta and tau proteins, might interfere with the communication dynamics of nerve cells across multiple regions of the brain that are important for memory and cognition. After mapping these changes, we will zoom in even further, and study the genetic and molecular signatures of individual brain cell subtypes, including both nerve and glia cells, to see whether, how and when they are impacted by disease. By integrating these multiscale insights, we aim to pinpoint comprehensively the specific cells and/or molecular pathways that may play key roles in early brain deficits that mark the initiation and progression of AD. In so doing, we hope to uncover new potential treatment targets for AD that go beyond the established focus on amyloid beta and tau.