Alzheimer's disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine efficacy in aged mice

BackgroundAlzheimer's disease (AD) patients are at greater risk of focal seizures than similarly aged adults, which may accelerate cognitive decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled model of chronic seizures allows for precisely timed drug administration studies to expediently evaluate efficacy and tolerability of investigational treatments in AD-associated mouse models.ObjectiveWe hypothesized that mechanistically distinct ASMs would differentially control seizures of aged AD mice (9-14 months), thereby informing rational ASM selection for AD.MethodsPSEN2-N141I and APP(swe)/PS1(dE9) mice underwent corneal kindling at 9-14 months old to quantify latency to kindled criterion versus matched wild-type mice. Dose-related response to commonly prescribed ASMs for older adults with epilepsy (valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin) was then assessed.ResultsSex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more kindling stimulations to reach criterion (χ(2) = 5.521; p < 0.05). Male APP/PS1 mice were no different in kindling rate versus controls, but did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive to valproic acid and lamotrigine.ConclusionsAD genotypes may differentially impact ASMs activity in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD to slow cognitive decline.