Amyloid-β: a potential link between epilepsy and cognitive decline

People with epilepsy — in particular, late-onset epilepsy of unknown aetiology — have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease (AD), supporting the concept of an epileptic AD prodrome. However, the relationship between epilepsy and cognitive decline remains controversial, with substantial uncertainties about whether epilepsy drives cognitive decline or vice versa, and whether shared pathways underlie both conditions. Here, we review evidence that amyloid-β (Aβ) forms part of a shared pathway between epilepsy and cognitive decline, particularly in the context of AD. People with epilepsy show an increased burden of Aβ pathology in the brain, and Aβ-mediated epileptogenic alterations have been demonstrated in experimental studies, with evidence suggesting that Aβ pathology might already be pro-epileptogenic at the soluble stage, long before plaque deposition. We discuss the hypothesis that Aβ mediates — or is at least a major determinant of — a continuum spanning epilepsy and cognitive decline. Serial cognitive testing and assessment of Aβ levels might be worthwhile to stratify the risk of developing dementia in people with late-onset epilepsy. If seizures are a clinical harbinger of dementia, people with late-onset epilepsy could be an ideal group in which to implement preventive or therapeutic strategies to slow cognitive decline. People with epilepsy have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease. Here, the authors review evidence that amyloid-β forms part of a shared pathway between epilepsy and cognitive decline. Key points Seizures and cognitive decline are interrelated: people with epilepsy have a threefold increased risk of dementia compared with the general population, and the risk is particularly high when the onset of epilepsy is in late adult life. Around 25% of people who develop epilepsy in late adulthood have no defined cause for their seizures, leading to the diagnosis of late-onset epilepsy of unknown aetiology (LOEU). People with LOEU have been shown to have amyloid pathology in the brain, with amyloid-β (Aβ) deposition increasing their risk of developing cognitive decline over the decades following seizure onset. Experimental studies support a role for Aβ in promoting seizures: Aβ is pro-epileptogenic at the oligomer stage, long before plaque deposition, and its accumulation fosters network hyperexcitability. Seizures c