Impact of Chronic Seizures on Neuropsychiatric Comorbidities in AD-Associated Models

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Abstract: Autosomal dominant early-onset Alzheimer's disease (ADEOAD) is associated with numerous genetic mutations, including those in amyloid precursor protein (APP), and presenilin (PSEN) 1 and 2 genes. Growing evidence indicates that patients with AD often experience undiagnosed focal seizures. Indeed, over 30% of AD patients with the most common PSEN2 gene variant (N141I) report seizures and patients with APP duplication have a similarly high incidence of reported seizures, suggesting an unexplored role of hyperexcitability in the pathophysiology of AD. Both epilepsy and AD are associated with numerous neuropsychiatric comorbidities. Limited clinical evidence suggests that AD patients with reported seizures may have worsened long-term disease trajectory. However, few studies have directly addressed how chronic seizures in the presence of AD-associated risk genes affect long-term neuropsychiatric and behavioral comorbidities. Even less data exists to directly define the age-dependent impact of chronic seizures on neuroplasticity processes, which may also underlie neuropsychiatric comorbidities of AD. This proposal will thus demonstrate how chronic seizures age-dependently impact neuropsychiatric comorbidities and neuroplasticity-associated protein expression in several preclinical models of AD that do and do not demonstrate amyloid-beta accumulation (APP/PSEN1 and PSEN2-N141I, respectively). This proposal will definitively address whether and when chronic seizures impact the functional and neuropathological sequelae of AD so as to elucidate whether seizures are a contributor to worsened AD trajectory. It is currently unclear when in the course of AD seizures occur. It is also unclear whether these seizures exacerbate neuropsychiatric symptoms associated with AD. ADEOAD-risk genes represent underexplored molecular contributors to network hyperexcitability, which may accelerate disease progression in the context of AD. The major goal of this project is to thus define the age-dependent additive impact of ADEOAD-associated risk factors and chronic seizures on the development and severity of neuropsychiatric comorbidities and neuroplasticity-associated protein expression.