ABSTRACT Electroencephalographic (EEG) abnormalities in Alzheimer’s disease are poorly understood and can provide insight into network changes accompanying disease progression and serve as non-invasive biomarkers. This proposal is based on a novel EEG abnormality that is common very early in life in mouse models of Alzheimer’s disease neuropathology. The abnormality consists of high frequency oscillations (HFOs), ultrafast (>250 Hz), and very brief (~30 ms) electrical events in the EEG. Notably, HFOs are known to occur in epilepsy but their role in Alzheimer’s disease models remains unknown. The goals of the proposed project are: (i) to determine the role of high frequency oscillations (HFOs) as a new type of abnormal Alzheimer’s disease-related electrical biomarker using electrode arrays, (ii) to manipulate HFOs in real time as a method to boost or repress memory, since impaired memory is a major symptom of Alzheimer’s disease and last (iii) to test an underlying mechanism contributing to HFOs in Alzheimer’s disease. In Aim 1 we will address the novel hypothesis that HFOs start as a local phenomenon in the hippocampus and progressively expand into more superficial areas as the mice get older. To this end, we will take advantage of a novel neurotechnology that uses flexible electrode arrays and a mouse model of cerebral amyloid overexpression that shows robust HFOs to record longitudinally. We will also test if HFOs precede other epileptiform abnormalities and reduced gamma power, which are commonly seen in Alzheimer’s disease. These experiments will tell us if HFOs can be considered an early biomarker. Furthermore, we will ask whether and how HFOs relate to the other abnormalities. In Aim 2 we will address the role of HFOs in impaired memory and test an underlying mechanism. We will use a novel closed-loop protocol we developed to detect and disrupt HFOs in real time to test whether selective disruption of HFOs during sleep is beneficial to memory and Alzheimer’s disease neuropathology. Importantly, our preliminary data suggest that the closed-loop approach improves memory in a mouse model of Alzheimer’s disease. To address mechanism, we will test a gene therapy approach to reduce HFOs in vivo by overexpressing a specific K+ channel and test if memory is improved. Notably, our pilot data suggest that overexpression of this K+ channel reduces HFOs in vivo. Effects of the closed-loop approach or K+ channel overexpression will be tested on HFOs and other epileptiform activity. Because HFOs occur during a sleep stage where Aβ is being cleared, we will also stain for soluble Aβ and ask if it is reduced when HFOs are disrupted. This project will address an unmet goal for new and improved biomarkers and two novel strategies to disrupt them using state-of-the-art methods. It also aims to provide a solid foundation for future investigation of HFOs in diverse models to address mechanisms and circuits that HFOs utilize in Alzheimer’s disease pathophys...