Instrumental, Neurophysiological, cognitive and Sleep InvestiGations into the High risk of neurodegeneraTion in Late Onset Epilepsy of Unknown aetiology: the INSIGHT-LOEU study.

Late-onset epilepsy (LOE) remains of unknown aetiology (LOEU) in around 20% of cases. Longitudinal studies have demonstrated the presence of early cognitive impairment at seizure onset, progressive memory decline and a substantially elevated risk of dementia within a decade of diagnosis, with an increased risk of subsequent neurodegenerative disorders, particularly Alzheimer's disease (AD). LOEU is associated with cognitive network alterations and epileptiform activity, although links remain unclear. Further emerging data suggest that neurodegenerative processes related to β-amyloid and tau pathology may precede the onset of epilepsy. Although epilepsy is highly prevalent among older adults, its impact on quality of life remains unclear, with affective symptoms and sleep disturbances as key determinants of subjective well-being. These findings suggest that LOEU should be reconceptualised as a multidimensional neurological condition. This protocol advocates an integrated approach, combining neuropsychological assessment, advanced biomarkers, neurophysiological measures and systematic sleep evaluation to identify high-risk phenotypes and define optimal windows for neuroprotective interventions in LOEU. This strategy could improve the early detection of cognitive decline, guide personalised management, and ultimately enhance quality of life, while contributing to the long-term sustainability of healthcare systems in an ageing population, focusing on LOEU as a model for dementia prevention.