<i>In vivo</i> tau in epilepsy reflects clinical severity and immune- and ageing-related proteomic changes

Tau pathology plays a central role in a number of neurodegenerative diseases, but its presence and relevance in epilepsy remain incompletely understood. Emerging evidence suggests that epilepsy may promote tau accumulation, yet whether this occurs in vivo, independent of comorbid dementia or amyloid pathology, is unclear. In this study, we combined [18F]flortaucipir (FTP) PET imaging with high-throughput plasma proteomics to characterise regional tau deposition and its clinical and molecular correlates in non-demented epilepsy patients. We enrolled 75 epilepsy patients and 47 age- and sex-matched healthy controls, collecting detailed clinical data, EEG features, and plasma samples for SOMAscan proteomic profiling, and plasma p-tau217, total tau, and amyloid-β measurement. A subset underwent FTP PET and [18F]florbetaben (FBB) PET imaging. Regional standardised uptake value ratios (SUVRs) were quantified using the AAL3 brain atlas. Compared to controls, epilepsy patients exhibited globally elevated FTP uptake across cortical regions, particularly in the lateral and medial frontal, lateral parietal, and lateral occipital brain areas, while FBB SUVRs showed nonsignificant differences. Exploratory analyses highlighted EEG slowing, multifocal discharges, and continued seizure activity during adolescence as clinical features associated with higher FTP SUVRs. In lateralised epilepsy, asymmetry indices tended to favour the hemisphere with the seizure onset zone. Plasma proteomic analysis identified 473 differentially expressed proteins in epilepsy, enriched in pathways related to immune activation, metabolism, and cytoskeletal remodelling. Protein expression associated with regional tau SUVRs again emphasised immune pathways as well as mitochondrial dysfunction; and suggested distinct mechanisms of tau accumulation in a region-specific manner. Furthermore, using the OrganAge algorithm, we found accelerated biological ageing in epilepsy patients across several organs, including the brain, heart, and muscle. While brain age gaps showed the strongest positive correlation with tau, the heart, pancreas, and muscle age gaps also showed correlations with regional brain tau, suggesting a link between systemic ageing and brain tau accumulation. Together, these findings suggest that epilepsy is associated with widespread elevated tau tracer signal that relates to EEG abnormalities, clinical disease burden, and immune- and ageing-related proteomic signatures. Our results raise the possibility that tau accumulation contributes to key aspects of epilepsy pathophysiology and may have relevance for biomarker development and future therapeutic targeting.