Our lab’s latest publication in the Journal of Alzheimer’s Disease explores how genetic models of Alzheimer’s disease (AD) affect seizure susceptibility and response to FDA-approved antiseizure medications (ASMs) in aged mice. This research addresses a critical gap in understanding how neurodegeneration intersects with epilepsy—especially in older adults.

People with AD are at higher risk for developing focal seizures, which can worsen cognitive decline and hasten mortality. Yet, it’s unclear whether standard ASMs are equally effective in the context of AD-related brain changes. To investigate, we used two mouse models of familial AD—PSEN2-N141I and APPswe/PS1dE9—at ages that reflect late-life physiology. We tested five ASMs – valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin – against seizures in these mouse models using a common evoked chronic seizure paradigm.

Our findings show that both genotype and sex influence seizure development and drug efficacy in aged mice:

• PSEN2-N141I mice, especially males, were less susceptible to seizures.
• APP/PS1 mice had more severe seizures despite similar kindling rates.
• Drug responses varied:
  • APP/PS1 mice were more sensitive to valproic acid, levetiracetam, and gabapentin.
  • PSEN2-N141I mice responded better to valproic acid and lamotrigine.

These results suggest that AD genotype plays a key role in both seizure risk and treatment outcomes. Personalized approaches to seizure management in AD may be more effective than current one-size-fits-all strategies. Furthermore, because ASMs are generally well-tolerated and safe in older people with epilepsy, it is likely that rationally selected ASMs will be similarly safe in older people with AD. However, further clinical studies are desperately needed.

This study contributes to our lab’s growing research on the intersection between Alzheimer’s disease and epilepsy. It also suggests that treating the “epileptic variant” in this patient population may be feasible.