This study investigates the shared proteomic signatures between Alzheimer's Disease (AD) and epilepsy, aiming to identify protein differences associated with both conditions. Using published proteomics datasets, the researchers found a significant overlap in protein alterations in the hippocampus of epilepsy patients and advanced AD patients, with 89% (689/777) of proteins altered in epilepsy also significantly altered in advanced AD. Of these, 340 proteins were altered in the same direction, while 216 were altered in opposite directions. Synapse and mitochondrial proteins were notably decreased in both conditions, suggesting common disease mechanisms. Ribosome proteins were increased in epilepsy but decreased in AD. Many proteins altered in epilepsy interact with tau or are regulated by tau expression, indicating that tau may mediate common pathological changes in both conditions. Immunohistochemistry for Aβ and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed increased intraneuronal pTau217 and pTau231 but no significant aggregates or plaques in epilepsy hippocampal sections. The study highlights the potential role of tau in mediating common protein changes in epilepsy and AD, providing insights into shared mechanisms and therapeutic opportunities.This study investigates the shared proteomic signatures between Alzheimer's Disease (AD) and epilepsy, aiming to identify protein differences associated with both conditions. Using published proteomics datasets, the researchers found a significant overlap in protein alterations in the hippocampus of epilepsy patients and advanced AD patients, with 89% (689/777) of proteins altered in epilepsy also significantly altered in advanced AD. Of these, 340 proteins were altered in the same direction, while 216 were altered in opposite directions. Synapse and mitochondrial proteins were notably decreased in both conditions, suggesting common disease mechanisms. Ribosome proteins were increased in epilepsy but decreased in AD. Many proteins altered in epilepsy interact with tau or are regulated by tau expression, indicating that tau may mediate common pathological changes in both conditions. Immunohistochemistry for Aβ and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed increased intraneuronal pTau217 and pTau231 but no significant aggregates or plaques in epilepsy hippocampal sections. The study highlights the potential role of tau in mediating common protein changes in epilepsy and AD, providing insights into shared mechanisms and therapeutic opportunities.