Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer's Disease: Unanswered Questions and Next Steps

Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer's disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed subclinical epileptiform activity (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we reviewkey unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.

Automated summary

Cortical network hyperexcitability in Alzheimer's disease (AD) can be targeted for therapeutic intervention. There is growing interest in studying the prevalence of subclinical epileptiform activity (SEA) in AD patients, including silent seizures and interictal epileptiform discharges (IEDs). SEA has been found to be common in AD, with estimates ranging between 22-54%. Modifying the hyperexcitable state in patients with AD may improve cognition, and recent clinical trial results suggest a therapeutic effect with levetiracetam administration. Further research is needed to define screening criteria, optimal screening methods, and personalized therapeutic intervention.