Personalized Synchronization of Cortical Rhythms to Improve Memory in Alzheimer's Disease

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is a severely debilitating disorder. It affects over 50 million people worldwide and its associated costs are estimated to exceed $305 billion annually. By mid-century, 153 million people are expected to be living with Alzheimer’s disease and costs are projected to surpass $1 trillion, as the global population rapidly ages. Impaired working memory is a central feature of the cognitive deterioration in Alzheimer’s disease and a primary driver of disability, placing sharp limits on social functioning, activities of daily living, and quality of life. Working memory refers to our ability to hold behaviorally useful information in mind over a period of seconds and is a fundamental building block of human cognition and the gateway to long-term memory. Neuroscience investigations have demonstrated that working memory function is subserved by oscillatory mechanisms in the healthy brain, and that specific patterns of synchronous oscillatory dynamics may be important for understanding the disease mechanisms of Alzheimer’s disease, consistent with the longstanding hypothesis of Alzheimer’s disease as a disconnection syndrome. Here, we examine the mechanisms of working memory impairment in Alzheimer’s disease from a physiologically inspired perspective centered on large-scale brain networks and how they interact through synchronized electrophysiological oscillations. We focus on established neural coding schemes (i.e., cross-frequency coupling and phase synchronization) hypothesized to index flexible large-scale circuits that integrate information across multiple temporal and spatial scales during cognition. We combine high-density electroencephalographic measurements of synchronized oscillations with personalized high-definition transcranial alternating-current stimulation to determine whether it is possible to modify components of frontotemporal networks and cause rapid improvements in working memory function. Our preliminary data are highly encouraging and indicate that we can causally modulate the synchronization of long-range low-frequency oscillations, increase local phase- amplitude coupling, and improve working memory capacity in people with Alzheimer’s disease to levels equivalent to that of demographically matched healthy controls. The goals of the research program are to use novel neuroscience tools and analytic procedures to gain a deeper understanding of the pathophysiology of memory impairment in Alzheimer’s disease, and achieve concrete translational progress toward the development of personalized, non-pharmacological interventions for improving memory and cognition in Alzheimer’s disease and related dementias.