Tracking the Onset and Progression of Cognitive Dysfunction Across Brain Regions

Aging changes the brain both structurally and functionally. These changes promote cognitive decline and increases the risk of Alzheimer’s disease (AD), a neurodegenerative disease that affects millions of Americans, and is the leading cause of dementia among adults. Many changes occur with aging that are associated with AD, such as the presence of amyloid beta plaques or tau tangles, but it is not clear what role they play in the onset and progression of clinical symptoms. This has led to disappointing results in clinical trials for AD treatment, including the recently FDA-approved aducanamab that reduces amyloid beta plaques but only has minimal effects on cognitive dysfunction. Distinguishing which features cause cognitive dysfunction and understanding their trajectories will be essential for diagnosing and treating patients effectively.

A major challenge in studying aging processes is that they can occur over years and heterogeneously across brain regions. Further complicating their study, pathological changes are thought to involve features as fast as the firing of neurons and as small as the phosphorylation of proteins.

Methodology that I established over the past year with K99 funding from the National Institute on Aging is able to overcome spatiotemporal limitations constraining the study of aging neural processes. The core of these efforts involves an innovative form of implantable electronics that I helped develop in my postdoctoral career. These bioinspired, neuron-like electronics allow longitudinal studies of aging-associated changes in single-neuron and circuit-level electrophysiology across brain regions. In recent work, I have utilized this technology to record brain activity from different regions in live, behaving animals in virtual reality as AD-related pathology develops and cognitive changes progress. This opens the door to experiments that were previously not possible which can help understand how aging changes neuronal networks and contributes to cognitive decline.