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 associated with AD appears to involve alteration of neuroinflammatory processes and inhibitory interneurons’ activity associated with 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, a growing body of literature has shown how 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 for up to 70 minutes after the end of a single stimulation session 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, the parent R01 award issued in 2018 is supporting a clinical trial investigating the impact of tACS on gamma oscillatory activity, as well as its effect on Aβ and p-tau clearance and cognition. The present administrative supplement will support the upgrade of our originally proposed solutions for monitoring of gamma activity, via an improved electroencephalography device, a transcranial magnetic stimulation platform for investigation of inhibitory and excitatory cortical circuitry, and a neuronavigation suite for accurate tracking of the biophysical impact of tACS on brain structures.