PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is a neurodegenerative disease that affects over 5 million Americans. Despite its clinical and public health impact, and the resources invested in treatment development, existing therapies remain only symptomatic (not disease modifying) and have modest efficacy. Disease models have traditionally emphasized molecular (maladaptive changes in -amyloid and tau proteins) and cellular (neurodegeneration) processes. Therefore, treatment development has focused on interventions that engage these molecular and cellular mechanisms, i.e. pharmacology and immunotherapy. Recent developments in pathophysiology, biomarker discovery and treatment development have emphasized a physiological approach to AD, with a focus on gamma oscillations as treatment targets. Critically, evidence in rodents suggests that engaging these aberrant physiological signatures with 40 Hz light and sound stimulation not only restores gamma oscillations and improves memory, but it also activates microglia leading to a reduction in amyloid and tau. Hence, this treatment strategy has the potential to be a disease-modifying therapy, which we are lacking in AD. While engaging gamma oscillations with 40Hz light and sound is a viable strategy, using electrical stimulation to modulate an electrical biological phenomenon should have greater impact. Noninvasive device neuromodulation technologies have been used as neuroscience tools to probe and study brain physiology in humans in vivo for decades, and as diagnostic procedures (e.g. TMS for clinical neurophysiology and presurgical mapping) and therapeutic interventions for neuropsychiatric conditions. tACS is very safe, well tolerared, cheap to manufacture and portable, making it a potentially home-based therapy. The capacity of tACS to engage oscillations in the human brain leading to changes in cognition, behavior and perception is established. That said, given the weak intensity of the electrical currents (e.g. 2mA), tACS may not always effectively engage or reduce ongoing oscillation in the brain. A more sophisticated and individualized “smart tACS” approach that uses closed-loop technology by reading the ongoing EEG activity of the patient and applying the stimulation in phase with the ongoing patient-specific brain activity is now technically possible, and showing to have greater impact on brain oscillations. We hypothesize that closed-loop tACS at 40 Hz in patients with AD should be a more effective strategy to engage these abnormal rhythms, and if the results in rodents translate to humans as early evidence suggests, it may become a much needed disease-modifying intervention (or at least a safe and cost-effective symptomatic treatment).