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

Nature Reviews Neurology volume 17, pages 469–485 (2021)Cite this article

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Abstract

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.

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 can be a harbinger of dementia, and identification of people at high risk of cognitive decline at epilepsy onset might allow crucial interventions early in Aβ deposition, thereby preventing further neurodegeneration.

  • Neuropsychological and biomarker assessment should be used to stratify patients with LOEU at an early stage to enable personalized treatment and potential enrolment in disease-modifying drug trials.

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Fig. 1: Aβ at the interface of epileptogenesis and neuronal loss.
Fig. 2: Aβ accumulation, late-onset epilepsy and cognitive decline.
Fig. 3: Aβ pathology, LOEU and neurodegeneration.

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Acknowledgements

A.S. is supported by the NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.

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Authors and Affiliations

  1. Neurology Clinic, Department of Medicine and Surgery, University of Perugia — S. Maria della Misericordia Hospital, Perugia, Italy

    Michele Romoli, Lucilla Parnetti & Cinzia Costa

  2. Oxford Epilepsy Research Group, NIHR Biomedical Research Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK

    Michele Romoli & Arjune Sen

  3. Neurology and Stroke Unit, “Maurizio Bufalini” Hospital, Cesena, Italy

    Michele Romoli

  4. IRCCS Istituto delle Scienze Neurologiche di Bologna, Neurologia e Rete Stroke Metropolitana, Ospedale Maggiore, Bologna, Italy

    Michele Romoli

  5. Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy

    Paolo Calabresi

  6. Fondazione Policlinico Universitario A. Gemelli, IRCCS, UOC Neurologia, Dipartimento di Scienze dell’Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Rome, Italy

    Paolo Calabresi

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M.R., A.S. and C.C. researched data for the article and drafted the paper. All authors contributed substantially to discussion of the article content and to the writing, review and editing of the manuscript before submission.

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Correspondence to Cinzia Costa.

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Competing interests

P.C. receives research support from Preston and Zambon to perform preclinical investigation on drugs that are not discussed in the text. A.S. has received research funding, speaker fees and/or honoraria from Bial Limited, Eisai Europe, GW Pharma, Livanova and Eisai. He is lead investigator on the Investigation of Levetiracetam in Alzheimer’s Disease Study (ILiAD), which is currently active but no data are yet available. M.R., C.C. and L.P. declare no competing interests.

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Nature Reviews Neurology thanks H. Tanila and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Review criteria

We selected references by searching PubMed, EMBASE and Cochrane CENTRAL for articles published in English before 1 February 2021, the main search string being “Alzheimer disease” or “cognitive decline”, and “late onset epilepsy”. Assorted combinations of the following terms were used to retrieve all papers: “epilepsy”, “late onset epilepsy”, “seizures”, “epileptiform activity”, “network hyperexcitability”, “epileptogenesis”, “epileptogenic”, “antiepileptic drugs”, “antiseizure medications”, “anticonvulsants”, “dementia”, “amyloid”, “amyloid precursor protein” or “APP”, “presenilin” or “PSEN”. We reviewed reference lists within original research and review articles for additional references through backward citation search. We finalized the reference list on the basis of originality and relevance to the scope of this Review. We focused on scientific literature in the English language published from 1990 onwards, but also included older publications of high value, merit or originality.

Glossary

Aβ-facilitated tauopathy

The hypothesis that Alzheimer disease (AD) is the trigger for the accumulation and spread of tau pathology, leading to overt neurodegeneration.

Late-onset epilepsy

Epilepsy that develops in late adult life. Cerebrovascular events, such as ischaemic or haemorrhagic stroke, are the main cause, but late-onset epilepsy might also arise from metabolic, infectious or structural (for example, neoplastic) disorders or dementia.

Aβ plaques

Aggregates of amyloid-β (Aβ) protein, which accumulate to form neuritic plaques during the course of Alzheimer disease (AD).

Late-onset epilepsy of unknown aetiology

(LOEU). Epilepsy that develops in late adult life in the absence of vascular, metabolic, infectious, structural or neurocognitive causes. Up to 20% of adults who develop epilepsy in late adulthood have an unknown cause; amyloid-β pathology might contribute to epilepsy and cognitive decline in these patients.

Epileptic prodromal AD

Retrospective definition denoting patients with an Alzheimer disease (AD) diagnosis preceded by seizures in adulthood.

Quantitative EEG analysis

Analysis of cortical connectivity and neuronal synchronization of rhythmic oscillations at various frequencies. Abnormalities in cortical connectivity can be used to detect patients with mild cognitive impairment and predict evolution to Alzheimer disease (AD).

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Romoli, M., Sen, A., Parnetti, L. et al. Amyloid-β: a potential link between epilepsy and cognitive decline. Nat Rev Neurol 17, 469–485 (2021). https://doi.org/10.1038/s41582-021-00505-9

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