Late-onset unexplained epilepsy is a potential harbinger of dementia, likely driven by network hyperexcitability that facilitates amyloid-β release and tau propagation. Dampening this activity with antiseizure medications offers a potential disease-modifying strategy, yet whether specific agents differentially alter this neurodegenerative trajectory remains unknown. Herein, we emulated a target trial using global real-world federated data on patients with late-onset unexplained epilepsy to compare dementia risk across antiseizure monotherapies. Using data from 94,250 patients, we found that sodium channel blockers were associated with a 27% lower hazard of incident all-cause dementia (HR=0.73, 95% CI 0.61–0.88) and 34% lower hazard of Alzheimer’s disease (HR=0.66, 0.49–0.88), compared with levetiracetam/brivaracetam. While the class effect was protective, individual agents such as phenytoin, carbamazepine, and lamotrigine showed divergent safety and efficacy profiles. We replicated these findings in both a Down syndrome cohort and the external National Alzheimer’s Coordinating Center dataset. 

Our results suggest that targeting neuronal excitability with sodium channel blockers is associated with slowing neurodegenerative progression, prioritizing the repurposing of these agents for dementia prevention trials.