Late-onset Unexplained Epilepsy as a Risk Factor for Dementia

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Project Summary / Abstract Late-onset unexplained epilepsy (LoUE), defined as epilepsy starting after age 55 with no clearly identified cause, has emerged as a significant risk factor for Alzheimer’s disease and related dementias (AD/ADRD). LoUE afflicts 50,000 new patients in the U.S. each year and will soon affect many more as our elderly population grows. Individuals presenting with LoUE have no prior history of dementia. Yet, LoUE is associated with a 2-3x increased risk of developing dementia, and up to 25% of LoUE develop dementia within 4 years after their first seizure. We have little understanding of the mechanisms underlying dementia in LoUE; no tools to predict which individuals with LoUE are at highest risk; and no treatments to prevent dementia in LoUE. 30-40% of LoUE may harbor AD pathology and/or occult cerebrovascular disease, and we hypothesize that these pathologies drive much of the increased dementia risk in LoUE. Yet, other pathologies and mechanisms are also possible and need to be identified. Our long-term goal is to develop a precision medicine approach to preventing dementia in LoUE, in which individualized risk assessment and disease subtyping can specifically inform a patient’s dementia prognosis and guide targeted therapies to reduce dementia risk. We hypothesize that rigorous, data-driven phenotyping of LoUE based on clinical features, biomarkers, and cognitive outcomes, will advance mechanistic understanding of dementia in LoUE and accelerate therapeutic development to reduce dementia risk. The goals of this proposal are to elucidate the risk factors and mechanisms that lead to dementia in LoUE and to develop tools for dementia risk-stratification in LoUE. To accomplish these goals, we will carry out a prospective, multi- center, longitudinal observational study of LoUE focused on understanding mechanisms and predicting outcomes of AD/ADRD in LoUE. We will enroll 600 participants with LoUE across 7 sites over 3 years. Participants will undergo a baseline evaluation with clinical history, cognitive testing, brain MRI, overnight EEG, and plasma AD biomarkers, and will be followed longitudinally with interval history every 6 months and annual cognitive testing. Our specific aims are: 1) To establish an unbiased framework for identifying mechanisms leading to dementia in LoUE, we will organize LoUE into disease subtypes based on: (a) associated neuropathology; (b) clinical phenotype; and (c) cognitive trajectory; 2) To advance mechanistic understanding of dementia in LoUE, we will identify epilepsy-related, neuropathologic, neurophysiologic, and structural features associated with development of dementia in LoUE; and 3) To enable prognostication of dementia in LoUE, we will develop practical clinical tools to forecast an individual’s risk of developing dementia after presentation with LoUE. This study will be the first large-scale study of LoUE that will define its relationship to AD/ADRD and have sufficient power to draw conclusions that will directly impact clinical care. This study will also establish foundational knowledge and risk-stratification tools that will facilitate the design of efficient and informative clinical trials for dementia prevention in LoUE.