Abstracts

This abstract has been invited to present during the Broadening Representation Inclusion and Diversity by Growing Equity (BRIDGE) poster session

Rationale: Adults with early-onset Alzheimer’s disease (EOAD) with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants are at heightened risk of seizures within 5 years of diagnosis versus non-affected age-matched individuals (Zarea et al, Neurology 2016). Yet whether there is heterogeneity in seizure susceptibility across the lifespan in the presence of EOAD-associated risk genes is unclear. Using two common models of evoked focal seizures, the minimal clonic and 6 Hz tests, we wanted to ascertain the degree to which seizure threshold changes with advanced age in two discrete EOAD-associated models: PSEN2 mice with the N141I Volga German variant versus APP^swe/PS1^dE9 mice that overexpresses amyloid beta (Aß). Critically, the PSEN2-N141I model does not demonstrate accumulated Aß whereas the APP/PS1 model shows increased Aß expression by ~6 months-old. We hypothesized that EOAD-associated variants would differentially modify focal seizure threshold with advanced age._x000D_
Methods: Male and female APP/PS1 and PSEN2-N141I and their respective wild-type (WT) counterparts were enrolled in seizure threshold testing at 2-months of age. Mice were assessed in each of the two seizure threshold tests once every 2 months until 10-12-months-old, with a minimum of 3 days between transcorneal electrical stimulations. Seizure-evoking corneal stimulations were delivered blinded to each genotype. Thresholds were defined using the staircase procedure wherein a minimum of two points were established between the limits of 0% and 100% of mice displaying a seizure in each test. The median convulsant current (CC50) and 95% confidence intervals (95% CI) was calculated for each age, genotype, and sex using Probit analysis. A subset of mice >10 months-old were then used for cFos immunohistochemistry of neuronal activation following 6 Hz seizure stimulation.

Results: Seizure threshold normally increases with advanced age (Engstrom et al, Epilepsia 1986). The threshold of male and female PSEN2-N141I mice demonstrated equivalent increases in seizure threshold with advanced age vs. age-matched WT mice in both the minimal clonic and 6 Hz focal seizure threshold test. The minimal clonic seizure threshold of male and female APP/PS1 mice similarly increased with advanced age relative to age-matched WT littermates. Notable blunting in age-related increases in 6 Hz seizure threshold of APP/PS1 mice were observed as early as 4-months-old in female mice (APP/PS1 CC50: 24.6 mA [22.2-26.9] vs. WT: 31.7 [27.8-36.9]) and by 8-months-old in male mice (APP/PS1: 39.2 mA [34.6-44.5] vs. WT: 53.6 mA [49.4-61.0]). The effect of genotype on cFos neuronal activation following 6 Hz stimulation will be further discussed.

Conclusions: This study suggests greater susceptibility to 6 Hz focal seizures in specific EOAD-associated models versus matched WTs. Further, this increased seizure susceptibility is evident across the lifespan in a sex-specific manner only in mice that overexpress Aß. Importantly, EOAD-associated risk genes do not equally increase seizure risk, suggesting that the heightened risk of seizures in EOAD may be an opportunity for precision medicine interventions.

Funding: AES Junior Investigator Award to MBH