APOE4 Promotes Tonic-Clonic Seizures, an Effect Modified by Familial Alzheimer’s Disease Mutations

Abstract

Seizures are emerging as a common symptom in Alzheimer’s disease (AD) patients, often attributed to high levels of amyloid β (Aβ). However, the extent that AD disease risk factors modulate seizure activity in aging and AD-relevant contexts is unclear. APOE4 is the greatest genetic risk factor for AD and has been linked to seizures independent of AD and Aβ. The goal of the present study was to evaluate the role of APOE genotype in modulating seizures in the absence and presence of high Aβ levels in vivo. To achieve this goal, we utilized EFAD mice, which express human APOE3 or APOE4 in the absence (EFAD−) or presence (EFAD+) of familial AD mutations that result in Aβ overproduction. When quantified during cage change day, we found that unlike APOE3, APOE4 is associated with tonic-clonic seizures. Interestingly, there were lower tonic-clonic seizures in E4FAD+ mice compared to E4FAD− mice. Restraint handing and auditory stimuli failed to recapitulate the tonic-clonic phenotype in EFAD mice that express APOE4. However, after chemical-induction with pentylenetetrazole, there was a higher incidence of tonic-clonic seizures with APOE4 compared to APOE3. Interestingly, the distribution of seizures to the tonic-clonic phenotype was higher with FAD mutations. These data support that APOE4 is associated with higher tonic-clonic seizures in vivo, and that FAD mutations impact tonic-clonic seizures in a paradigm dependent manner.

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

“…Due to the increased risk of seizure associated with APOE genotype [ 41 , 44 ] and its impact on brain development [ 6 ], we evaluated APOE genotype in SUDC cases from previous WES [ 22 ]. Among the 19 SUDC cases, there was 1 APO E2/E3 case, 11 E3/E3, 5 E3/E4, and 2 E4/E4.…”

“…Traumatic brain injury in pediatric cases with the E4 allele were also associated with poor outcome when compared to cases without E4 [ 34 ]. Furthermore, seizures are more common in individuals with the E4 allele [ 41 , 44 ]. However, we did not observe increased prevalence of E4 carriers among cases with FS or motor/developmental delay.…”

“…Previous WES analyses in SUDC cases [ 22 ] were reviewed for APOE variants to determine significance in this population, as there is increased risk of seizure associated with APOE genotype [ 41 , 44 ], impact on brain development [ 6 ], and poor outcome after traumatic brain injury [ 34 ]. Briefly, GATK Haplotype caller with depth ≥ 10 and alternate counts ≥ 5 was used to annotate variants.…”

Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s

“…Circuit hyperexcitability is a prodromal indicator in familial and late-onset AD (Dickerson et al, 2005;Hämäläinen et al, 2007;Miller et al, 2008;Sperling et al, 2010;Busche and Konnerth, 2015;Lamoureux et al, 2021;Minkeviciene et al, 2009;Nuriel et al, 2017;Quiroz et al, 2010;Sepulveda-Falla et al, 2012). Altered PV interneuron firing occurs at early stages of the disease (Hijazi et al, 2019;Petrache et al, 2019), likely contributing to epileptiform activity and overall circuit hyper-synchrony in cortex.…”

“…Several alternative models for early cognitive decline are under consideration (De Strooper and Karran, 2016) including abnormal circuit activity (Busche and Konnerth, 2015;Busche et al, 2008;Cirrito et al, 2005;Davis et al, 2014;Pooler et al, 2013;Wu et al, 2016). Circuit hyperexcitability is evident in several mouse models of familial (FAD) and sporadic AD (Lamoureux et al, 2021;Minkeviciene et al, 2009;Nuriel et al, 2017) including at prodromal stages (Bai et al, 2017;Busche and Konnerth, 2015). Furthermore, abnormal brain activity is apparent in humans with mild cognitive impairment (Dickerson et al, 2005;Hämäläinen et al, 2007;Miller et al, 2008;Sperling et al, 2010) and in early FAD (Quiroz et al, 2010;Sepulveda-Falla et al, 2012).…”