Abstract Objective People with early-onset Alzheimer’s disease (AD) are at elevated seizure risk. Further, chronic seizures in pre-symptomatic stages may disrupt serotonin pathway-related protein expression, precipitating the onset of AD-related pathology and burden of neuropsychiatric comorbidities. Methods 2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control mice were sham or corneal kindled for 2 weeks to model chronic seizures. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid β levels in hippocampus and prefrontal cortex were quantified. Results APP/PS1 mice experienced worsened mortality versus kindled Tg-controls. APP/PS1 females were also more susceptible to chronic kindled seizures. These changes correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression compared to controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice exhibited amyloid β overexpression and glial overactivity without plaque deposition. PSEN2 protein expression was AD model-dependent. Significance Seizures evoked in pre-symptomatic APP/PS1 mice promotes premature mortality in the absence of pathological Aβ deposition. Disruptions in serotonin pathway metabolism are associated with increased glial reactivity and PSEN2 downregulation without amyloid β deposition. This study provides the first direct evidence that seizures occurring prior to amyloid β plaque accumulation worsen disease burden in an AD genotype-specific manner. Highlights: Seizures are a comorbidity in Alzheimer’s disease that may worsen disease burden. Pathological overlap between both neurological disorders is understudied. Young APP/PS1, but not PSEN2-N141I mice, have increased seizure-induced mortality. Seizures reduce hippocampal serotonin pathway proteins only in young APP/PS1 mice. Kindled young APP/PS1 mice have glial hyperactivity before amyloid β accumulation.

Chronic seizure-induced serotonin pathway dysregulation coincides with mortality in Alzheimer’s disease mouse models