PROJECT SUMMARY/ABSTRACT Incident epilepsy is more common in the elderly than at any other time of life. While some cases are due to stroke or known Alzheimer’s disease (AD), many cases have no known etiology. This proposal hypothesizes that late-onset epilepsy (LOE; epilepsy starting at age 60 or later, in the absence of stroke or other identified cause) is associated with cognitive decline and preexisting neuropathology such as amyloid deposition; i.e., LOE may be a marker for future cognitive impairment and dementia. The research will use data from the ongoing longitudinal Atherosclerosis Risk in Communities (ARIC) cohort study (Aims 1 and 2), as well as from a new cohort recruited as part of this grant (Aims 3 and 4). The specific aims are: 1) To test the hypothesis that late-onset epilepsy (LOE) is associated with cognitive decline, and the subsequent development of MCI or dementia. 2) To test whether Aβ 42/40 ratio is associated with LOE. 3) To determine whether individuals with clinically-identified LOE have lower cognitive scores than individuals without LOE. 4) (Exploratory) To compare AD biomarkers in patients with and without LOE, and correlate subclinical epileptiform activity with cognitive performance in patients with LOE. Defining whether there is an association of LOE with an elevated risk of future cognitive impairment could allow patients to have earlier interventions, which may help slow future cognitive decline. This is an application for a Mentored Patient-Oriented Research Career Development Award (K23). The overarching training goal of the proposed project is to provide the candidate with the skills necessary to become an independent researcher in epilepsy related to aging. Specific training goals are to obtain advanced training in epidemiology and biostatistics; to obtain training in recruiting and leading cohort studies; to acquire and apply knowledge of AD pathophysiology and the use of biomarkers; to gain didactic and experiential training in cognitive assessments in neurodegenerative diseases; and to advance professional development skills in preparing manuscripts and presenting at conferences. The career development plan includes classes in biostatistics and epidemiology at the Johns Hopkins School of Public Health; regular meetings with mentors; seminars in biostatistics and the epidemiology of aging; seminars in AD pathophysiology and research; and attending/presenting at national conferences. The candidate’s primary appointment is in the Johns Hopkins Department of Neurology, an extremely supportive environment with a strong history of junior investigators successfully transitioning to independent investigators.