Abstracts

Rationale: Early-onset Alzheimer’s disease (EOAD) is associated with mutations in one of three risk genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). EOAD patients are at greater seizure risk than similarly aged adults. Older people with epilepsy generally respond well to antiseizure medications (ASMs); some ASMs may even confer cognitive benefit. However, little is known about whether mechanistically distinct ASMs may differentially control seizures in discrete EOAD populations (Lehmann et al, Neurochem Res 2021). The corneal kindled mouse model of epilepsy allows for the precise timing of seizure onset in a chronically seizing brain to quantify the efficacy of ASMs against secondarily generalized focal seizures. We thus hypothesized that mechanistically distinct ASMs would exert divergent efficacy against evoked secondarily generalized focal seizures in aged EOAD-associated mice (10-14 months) to define whether rational ASM selection may benefit specific EOAD populations._x000D_
Methods: Aged male and female EOAD-associated mice were corneal kindled: PSEN2-variant vs age-matched non-transgenic wild-type (WT) C57Bl/6J mice, and APP/PS1 vs. WT littermates. Seizure susceptibility was quantified as the number of stimulations required to present with a first generalized seizure and the number of stimulations required to reach kindling criterion (five consecutive Racine stage 5 seizures). Fully kindled mice then underwent pharmacological profiling over the course of 2-3 months using selected mechanistically distinct ASMs that are frequently used in older adults with epilepsy: valproic acid, levetiracetam, lamotrigine, diazepam, phenobarbital, and gabapentin. Dose-related ASM efficacy was then compared in each EOAD model vs. its respective WT.

Results: Sex and EOAD genotype differentially impacted kindling acquisition. Male PSEN2-variant mice took significantly more stimulations to have both a first generalized seizure (χ²=12.26; p< 0.01) and to reach criterion (χ²=8.488; p< 0.01) vs. age-matched WT mice. Female PSEN2-variant mice also took significantly more stimulations to have a first generalized seizure (χ²=4.360; p< 0.05), however there was no change in kindling acquisition rate. Conversely, kindling rate was no different between male or female APP/PS1 mice and WT littermates. Pharmacological profiling revealed significant, ASM mechanism-specific differences in acute seizure control between EOAD-associated models. Both male and female APP/PS1 mice were more sensitive to valproic acid, levetiracetam, and gabapentin than WT mice. Valproic acid and lamotrigine were more potent in PSEN2-variant mice vs. WT, regardless of sex._x000D_