Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums

A growing body of evidence has demonstrated a link between Alzheimer disease (AD) and epilepsy. Late-onset epilepsy and epileptiform activity can precede cognitive deterioration in AD by years, and its presence has been shown to predict a faster disease course. In animal models of AD, amyloid and tau pathology are linked to cortical network hyperexcitability that precedes the first signs of memory decline. Thus, detection of epileptiform activity in AD has substantial clinical importance as a potential novel modifiable risk factor for dementia. In this Review, we summarize the epidemiological evidence for the complex bidirectional relationship between AD and epilepsy, examine the effect of epileptiform activity and seizures on cognition in people with AD, and discuss the precision medicine treatment strategies based on the latest research in human and animal models. Finally, we outline some of the unresolved questions of the field that should be addressed by rigorous research, including whether particular clinicopathological subtypes of AD have a stronger association with epilepsy, and the sequence of events between epileptiform activity and amyloid and tau pathology. Growing evidence suggests a bidirectional relationship between Alzheimer disease and epilepsy. This Review summarizes the epidemiological evidence and explores the potential mechanisms that underlie the effects of epileptiform activity on cognition in people with Alzheimer disease. Pathological neuronal hyperexcitability in individuals with Alzheimer disease is two to three times higher than in healthy individuals and is associated with accelerated cognitive deterioration.Late-onset epilepsy might be a non-cognitive prodromal sign of Alzheimer disease and a novel modifiable risk factor.Neuropsychological testing in late-onset epilepsy as well as long-term EEG in early Alzheimer disease is necessary to ensure timely antidementia and/or antiseizure interventions.Studies in transgenic Alzheimer disease mouse models have revealed cellular and molecular mechanisms linking neuronal hyperexcitability to amyloid and tau pathology, and have demonstrated that hyperexcitability can accelerate disease progression.Epilepsy in Alzheimer disease is a hard-to-treat condition. Experimental and clinical studies have found levetiracetam to be the most promising antiseizure medication among currently available compounds.