PROJECT SUMMARY / ABSTRACT There have been no new treatments approved for Alzheimer’s disease (AD) over the past 15 years. It is estimated that by the year 2050, AD will affect 14 million Americans and cost the nation over $1 trillion annually. A fresh perspective on AD is needed, to uncover new disease mechanisms that drive cognitive decline in AD, and to identify new treatment targets for more successful drug development. This pilot study will investigate a novel brain electrical abnormality that was recently discovered in two AD patients who underwent intracranial recordings with foramen ovale electrodes (FOEs). FOEs are a safe and minimally invasive means to obtain high fidelity recordings of electrical activity from the mesial temporal lobes (mTL), one of the first brain regions affected by AD pathology. FOE recordings from these AD patients revealed abundant mTL epileptiform discharges and frequent seizures occurring during sleep. The vast majority of this epileptiform activity was silent, occurring without any overt clinical symptoms and without any visible signs on scalp EEG. Whether silent mTL epileptiform activity is common in early stages of AD, and whether this activity contributes to memory impairment in AD is unknown, because AD patients almost never undergo the intracranial recordings needed to detect this activity. The goal of this proposal is to further investigate the role of silent mTL epileptiform activity in early stages of AD. The over-arching hypothesis is that there exists a subset of AD patients in whom silent mTL epileptiform activity is a potent and modifiable contributor to cognitive decline. If true, reduction of this activity could comprise a new treatment target for symptomatic relief or disease modification in AD. This study will be performed at the Massachusetts General Hospital (Boston, MA) and Baylor Medical Center / St. Luke’s Hospital (Houston, TX). Eight participants with amnestic mild cognitive impairment or mild dementia due to AD will be recruited to undergo insertion of FOEs, followed by 3 days of continuous recordings with FOEs and scalp EEG. Recordings will be analyzed to characterize any silent mTL epileptiform abnormalities present and to correlate these findings with clinical and scalp EEG features. The specific aims of this study are: 1) Identify and characterize the spectrum of clinically silent mTL activity that occurs in early stages of AD; 2) Demonstrate the feasibility of recruiting and recording AD participants with FOEs, and determine the relationship between the duration and yield of these recordings; and 3) Assess clinical and scalp EEG features common to AD patients with silent mTL epileptiform activity. In the long term, this research has the potential to reveal a novel and potentially treatable neurophysiologic mechanism by which memory function becomes disrupted in early stages of AD. The data obtained here will be used to guide the design of larger studies using intracranial recordings...