Late-onset unexplained epilepsy with dual amyloid and tau negativity: are alpha-synuclein seed amplification assays the next diagnostic step?

Late-onset epilepsy of unknown etiology (LOEU) is associated with an increased risk of dementia. Current biomarkers, including cerebrospinal fluid (CSF) and positron emission tomography (PET) assessments for amyloid and tau, often fail to predict cognitive decline in a substantial proportion of LOEU patients. This case report presents a 67-year-old man with LOEU who later developed dementia with Lewy bodies (DLB). As cognitive decline progressed, emerging mild clinical features raised suspicion for DLB. Notably, cerebrospinal fluid analysis at this stage revealed negative amyloid and tau biomarkers but was positive for pathological alpha-synuclein using alpha-synuclein seed amplification assay (CSF ASyn-SAA). This finding highlights the potential clinical utility of CSF ASyn-SAA in achieving both earlier and more accurate DLB diagnosis. For LOEU patients exhibiting early signs of synucleinopathy, incorporating CSF ASyn-SAA into diagnostic panels could significantly improve diagnostic certainty, prognostic stratification, and opportunities for targeted therapeutic interventions. Further research is needed to investigate the yield of adding ASyn-SAA to CSF dementia panels in people with LOEU and progressive cognitive symptoms.