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Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums

Nature Reviews Neurology volume 20, pages 162–182 (2024)Cite this article

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Abstract

A growing body of evidence has demonstrated a link between Alzheimer disease (AD) and epilepsy. Late-onset epilepsy and epileptiform activity can precede cognitive deterioration in AD by years, and its presence has been shown to predict a faster disease course. In animal models of AD, amyloid and tau pathology are linked to cortical network hyperexcitability that precedes the first signs of memory decline. Thus, detection of epileptiform activity in AD has substantial clinical importance as a potential novel modifiable risk factor for dementia. In this Review, we summarize the epidemiological evidence for the complex bidirectional relationship between AD and epilepsy, examine the effect of epileptiform activity and seizures on cognition in people with AD, and discuss the precision medicine treatment strategies based on the latest research in human and animal models. Finally, we outline some of the unresolved questions of the field that should be addressed by rigorous research, including whether particular clinicopathological subtypes of AD have a stronger association with epilepsy, and the sequence of events between epileptiform activity and amyloid and tau pathology.

Key points

  • Pathological neuronal hyperexcitability in individuals with Alzheimer disease is two to three times higher than in healthy individuals and is associated with accelerated cognitive deterioration.

  • Late-onset epilepsy might be a non-cognitive prodromal sign of Alzheimer disease and a novel modifiable risk factor.

  • Neuropsychological testing in late-onset epilepsy as well as long-term EEG in early Alzheimer disease is necessary to ensure timely antidementia and/or antiseizure interventions.

  • Studies in transgenic Alzheimer disease mouse models have revealed cellular and molecular mechanisms linking neuronal hyperexcitability to amyloid and tau pathology, and have demonstrated that hyperexcitability can accelerate disease progression.

  • Epilepsy in Alzheimer disease is a hard-to-treat condition. Experimental and clinical studies have found levetiracetam to be the most promising antiseizure medication among currently available compounds.

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Fig. 1: An overview of observational studies on the risk of epilepsy in Alzheimer disease.
Fig. 2: EEG recording of epileptiform activity in two people with Alzheimer disease.
Fig. 3: Hippocampal giant spikes in a mouse model of Alzheimer disease.
Fig. 4: Amyloid-β and p-tau induce changes in cellular excitability.
Fig. 5: The interrelation between Alzheimer disease pathology and epileptiform activity.

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Acknowledgements

The authors are very grateful to G. Buzsáki and L. Mucke for their comments and constructive criticisms on an earlier draft of the manuscript. The authors are thankful to J. Cole and S. J. Damberger for their intellectual contribution to the article.

Author information

Authors and Affiliations

  1. National Institute of Mental Health, Neurology and Neurosurgery, Budapest, Hungary

    Anita Kamondi & Andras Attila Horvath

  2. Department of Neurology, Semmelweis University, Budapest, Hungary

    Anita Kamondi

  3. Department of Neurology, University of New Mexico, Albuquerque, NM, USA

    Madeleine Grigg-Damberger

  4. Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany

    Wolfgang Löscher

  5. A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland

    Heikki Tanila

  6. Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary

    Andras Attila Horvath

Authors
  1. Anita Kamondi
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  2. Madeleine Grigg-Damberger
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  3. Wolfgang Löscher
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  4. Heikki Tanila
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  5. Andras Attila Horvath
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Contributions

A.K. developed the primary content and structure of the article. All authors selected the references for the article. A.K. and A.A.H. wrote the first draft of the manuscript. AK., A.A.H., W.L. and H.T. prepared the figures and tables for the manuscript. All authors reviewed and/or edited the final version of the manuscript before submission.

Corresponding author

Correspondence to Anita Kamondi.

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Competing interests

A.K. received grant from the Hungarian Academy of Sciences, National Brain Research Program III (NAP2022-I-9/2022). M.G.-D. receives book royalties from Oxford University Press, and article royalties from Up-to-Date; and is Associate Editor of the Journal of Clinical Neurophysiology and Journal of Clinical Sleep Medicine. She received honoraria for presentations at the annual meeting of the American Academy of Sleep Medicine, and for teaching presentations at the annual meeting and fall course of the American Clinical Neurophysiology Society. W.L. received grants from the German Research Foundation (LO 274/15-1; 274/16-2); consultancy fees from AC Immune, Angelini Pharma, Clexio Biosciences, Lundbeck and Selene Therapeutics. He is co-founder and Chief Scientific Officer of PrevEp Inc. (Bethesda, MD). PrevEp is focusing on preventing epilepsy after traumatic brain injury, stroke and encephalitis. The company is not developing any current therapies to prevent epilepsy in Alzheimer disease, and none of its professional activities has any relationship to Alzheimer disease. H.T. received grants from the Academy of Finland (310059 and 340377), Jane and Aatos Erkko Foundation (Finland), and Olav Thon Foundation (Norway). A.A.H. received grants from the Hungarian Academy of Sciences, National Brain Research Program III (NAP2022-I-9/2022) and Momentum Research Grant (Lendület-2023_94); the Hungarian Scientific Research Fund 2019 of the National Research, Development and Innovation Office (PD-132652); a János Bolyai Research Scholarship of the Hungarian Academy of Sciences (bo-78-20-2020); the EU Joint Program Neurodegenerative Disease Research (JPND) project (via the National Research, Development and Innovation Office, 2019-2-1-7-ERA-NET-2020-00006).

Peer review

Peer review information

Nature Reviews Neurology thanks Benjamin Cretin, Jin-Tai Yu and Cinzia Costa for their contribution to the peer review of this work.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria Authors reviewed the scientific literature from 1 January 2017 to 15 October 2023, published in English, by searching PubMed, Scopus, Web of Science, Cochrane Library, EMBASE, CINAHL Plus, Science Direct, DOAJ and Google Scholar databases. Search terms included: Alzheimer’s disease; epilepsy; spike; seizures; epileptiform (activity); anticonvulsants; antiseizure drugs; antiepileptic drugs; (network) hyperexcitability; tau; amyloid; Alzheimer’s disease and epilepsy; and sleep. Although epilepsy occurs frequently in genetically determined early-onset Alzheimer disease this entity is not covered in this Review; therefore related papers were excluded. Seminal references published before 2017 were also included. Information about clinical trials were obtained from ClinicalTrials.gov.

Related links

Alzheimer’s Disease Neuroimaging Initiative database: https://adni.loni.usc.edu/

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Kamondi, A., Grigg-Damberger, M., Löscher, W. et al. Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums. Nat Rev Neurol 20, 162–182 (2024). https://doi.org/10.1038/s41582-024-00932-4

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