This study investigates the shared proteomic signatures between Alzheimer's disease (AD) and epilepsy. Using published proteomic datasets, the researchers found a significant overlap in protein changes in the hippocampus of epilepsy patients and advanced AD patients. Approximately 89% of proteins altered in epilepsy were also significantly altered in AD. Of these, 340 proteins were altered in the same direction, while 216 were altered in the opposite direction. Synapse and mitochondrial proteins were notably decreased in both conditions, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Many proteins altered in epilepsy interact with tau or are regulated by tau expression, suggesting that tau may mediate common protein changes in both diseases. Immunohistochemistry for Aβ and phosphorylated tau species showed increased intraneuronal pTau217 and pTau231 in epilepsy but no phosphorylated tau aggregates or amyloid plaques. The study highlights the potential role of tau in mediating common pathological protein changes in epilepsy and AD. The findings suggest that tau may be a key upstream regulator involved in the decrease of many neuronal proteins in epilepsy and that tau may mediate many of these effects via protein-protein interactions. The study also identifies distinct molecular mechanisms between the two diseases, with ribosomal subunits forming the most prominent cluster of proteins that were increased in epilepsy but decreased in AD. The results provide insights into common mechanisms in epilepsy and AD and highlight the importance of tau in these diseases. The study has limitations, including the use of existing proteomic datasets and the potential influence of age on protein similarities. Overall, the study supports the hypothesis that there are common molecular mechanisms involved in epilepsy and AD, with tau playing a key role in mediating these changes. The findings suggest that future AD therapeutics could be beneficial in epilepsy and vice versa.This study investigates the shared proteomic signatures between Alzheimer's disease (AD) and epilepsy. Using published proteomic datasets, the researchers found a significant overlap in protein changes in the hippocampus of epilepsy patients and advanced AD patients. Approximately 89% of proteins altered in epilepsy were also significantly altered in AD. Of these, 340 proteins were altered in the same direction, while 216 were altered in the opposite direction. Synapse and mitochondrial proteins were notably decreased in both conditions, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Many proteins altered in epilepsy interact with tau or are regulated by tau expression, suggesting that tau may mediate common protein changes in both diseases. Immunohistochemistry for Aβ and phosphorylated tau species showed increased intraneuronal pTau217 and pTau231 in epilepsy but no phosphorylated tau aggregates or amyloid plaques. The study highlights the potential role of tau in mediating common pathological protein changes in epilepsy and AD. The findings suggest that tau may be a key upstream regulator involved in the decrease of many neuronal proteins in epilepsy and that tau may mediate many of these effects via protein-protein interactions. The study also identifies distinct molecular mechanisms between the two diseases, with ribosomal subunits forming the most prominent cluster of proteins that were increased in epilepsy but decreased in AD. The results provide insights into common mechanisms in epilepsy and AD and highlight the importance of tau in these diseases. The study has limitations, including the use of existing proteomic datasets and the potential influence of age on protein similarities. Overall, the study supports the hypothesis that there are common molecular mechanisms involved in epilepsy and AD, with tau playing a key role in mediating these changes. The findings suggest that future AD therapeutics could be beneficial in epilepsy and vice versa.