LOEU should be reconceptualised as a multidimensional neurological condition, and an integrated approach combining neuropsychological assessment, advanced biomarkers, neurophysiological measures, and systematic sleep evaluation is advocated to identify high-risk phenotypes and define optimal windows for neuroprotective interventions.
Late-onset epilepsy remains of unknown aetiology (LOEU) in approximately 20% of cases.
LOEU is associated with early cognitive impairment at seizure onset, progressive memory decline, and a substantially elevated risk of dementia within a decade of diagnosis.
Emerging data suggest that neurodegenerative processes related to β-amyloid and tau pathology may precede the onset of epilepsy in LOEU.
LOEU is associated with cognitive network alterations and epileptiform activity, though the links between these phenomena remain unclear.
Affective symptoms and sleep disturbances are identified as key determinants of subjective well-being in older adults with epilepsy.
The INSIGHT-LOEU study proposes an integrated multimodal protocol combining neuropsychological assessment, advanced biomarkers, neurophysiological measures, and systematic sleep evaluation to characterize high-risk LOEU phenotypes.
The INSIGHT-LOEU protocol aims to contribute to long-term healthcare sustainability by using LOEU as a model for dementia prevention in an ageing population.
This research describes a study protocol called INSIGHT-LOEU, designed to investigate a specific type of epilepsy that begins later in life (typically after age 60) and has no identifiable cause—known as late-onset epilepsy of unknown aetiology (LOEU). About 1 in 5 people with late-onset epilepsy fall into this category. What makes LOEU particularly concerning is that people diagnosed with it appear to already show memory and thinking problems at the time of their first seizure, and these problems tend to worsen over time, with a significantly higher chance of developing dementia—especially Alzheimer's disease—within ten years of diagnosis. Emerging evidence suggests that the brain changes associated with Alzheimer's disease, such as the buildup of toxic proteins called beta-amyloid and tau, may actually begin before the epilepsy even starts, meaning epilepsy could be an early warning sign of an underlying brain disease rather than a separate condition. The INSIGHT-LOEU protocol responds to these concerns by proposing a comprehensive, multi-pronged evaluation of LOEU patients. Rather than focusing only on seizure control, the approach combines detailed memory and thinking tests, blood and spinal fluid biomarkers for Alzheimer's-related proteins, brain wave recordings, and thorough sleep assessments. Sleep disturbances and mood problems are also highlighted as important factors affecting the quality of life of people with LOEU, but these have often been overlooked. By systematically studying all these dimensions together, the researchers hope to identify which patients are at highest risk of cognitive decline and find the best timing for interventions that might protect the brain. This research suggests that LOEU should no longer be viewed simply as an unexplained seizure disorder, but rather as a complex, multi-dimensional neurological condition that may serve as an early window into the development of Alzheimer's disease. If successful, the INSIGHT-LOEU approach could lead to earlier identification of people at risk for dementia, more personalised treatment strategies, and ultimately better quality of life for older adults with epilepsy—while also helping healthcare systems better prepare for the growing challenge of dementia in an ageing global population.
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Upload Your LabsBergamo G, Fernandes M, Maio S, Albanesi G, Antonucci M, Barbaro I, et al.. (2026). Instrumental, neurophysiological, cognitive and sleep investigations into the high risk of neurodegeneration in late onset epilepsy of unknown aetiology: The INSIGHT-LOEU study.. Mechanisms of ageing and development. https://doi.org/10.1016/j.mad.2026.112237