Project Summary Thanks to advances in public health and medicine, the life expectancy of the world population continues to lengthen. While longer lifespan is a unique opportunity for society to benefit from the wisdom and experience of the elderly, aging is however also the greatest risk factor for neurodegenerative disorders such as Alzheimer's disease (AD). A fundamental neurobiological substrate of cognitive decline and neurodegeneration appears to involve alteration of neuroinflammatory processes with associated deposition of aberrant proteins, such as amyloid- β (Aβ) and phosphorylated tau (p-tau). Recent pre-clinical work from MIT's Li-Huei Tsai, Ed Boyden and collaborators reveals that induction of gamma oscillations in mice can modulate activity of microglia, modify inflammatory brain processes, and lead to clearance of Aβ and p-tau deposition. Translation of such findings to humans could have transformative impact. In recent years, transcranial Alternating Current Stimulation (tACS) has been shown effective in modulating brain activity and cortical rhythmic activity by means of low-amplitude alternating (sinusoidal) currents applied transcranially. In humans, work at the Berenson-Allen (BA) Center and elsewhere reveals that tACS can be applied safely if appropriate guidelines are followed, and that when applied at the appropriate alternating frequency it is possible to entrain gamma oscillations and enhance cognition. Furthermore, repeated sessions of tACS on consecutive days are safe and lead to an additive effect with longer lasting neuromodulatory impact on brain oscillation. Given the potential for gamma entrainment in humans via tACS, we propose a first- to-human translation of the preclinical data on the effect of induction of gamma oscillations on Aβ and p-tau in patients with mild to moderate AD, leveraging the close collaboration with Georges El Fakhri, director of the Gordon Center for medical imaging at MGH. Our central hypothesis is that repeated daily sessions of gamma-tACS in patients with AD will significantly decrease Aβ plaques and p-tau deposition in neurofibrillary tangles as measured by PET imaging. This will be correlated with changes on electrophysiological (EEG) measures of brain function, and on cognitive testing. This pilot study will provide the critical first step in the development of a novel intervention to prevent and treat AD, demonstrating the potential mechanisms of action, establishing a dose response relation, and informing the design of an eventual clinical trial.