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Late onset epilepsy and neurodegeneration

Late-onset epilepsy patients seem to have an increased risk of developing dementia. The Ballerini et al. prospective study showed normal neurodegenerative biomarkers and no abnormal cortical atrophy pattern in patients with late-onset temporal lobe epilepsy compared to patients with mild cognitive impairment. Further researchs are needed to identify risk profiles for developing dementia in individuals with late-onset-epilepsy. Recently, several risk factors relative to an increased risk of late-onset epilepsy were identified in patients with cognitive decline.

Late-onset epilepsies are increasingly considered a prominent topic in research due to the growing average age of the world population, especially in relation to the increased risk of developing dementia in patients with epilepsy.
According to studies on the brain tissue of people with epilepsy, neurodegenerative biomarkers may be linked to the pathophysiology of epilepsies. This knowledge inspired researchers to explore new possible therapeutic options as a disease-modifying treatment in epilepsy patients targeting pathological protein accumulation, (1).
Ballerini et al. (2) explored this topic in a prospective study aimed to characterize the pattern of cortical atrophy, assessed through MRI, and cerebrospinal fluid (CSF) biomarkers of Alzheimers disease (AD) in patients with temporal lobe epilepsy, onset after the age of 50 and no cognitive impairment (LO-TLE). This group was compared to three groups (data collected retrospectively): healthy controls, patients with Mild Cognitive Impairment (MCI) and abnormal CSF (AD biomarkers), and patients with MCI and normal CSF AD biomarkers. LO-TLE group was found to have neurodegenerative biomarkers in the normal range; only four LO-TLE individuals (20%) had abnormally low CSF Aβ1–42 levels (none showed abnormal Aβ1–42: Aβ11–40 ratio) and three (15%) had abnormal tTAU. The comparison highlighted that cortical and subcortical thickness did not differ between epilepsy patients and controls. MCI patients showed diffuse cortical atrophy and MCI-AD patients reduced subcortical volumes. These results, that may seem partly contrary to the idea of a close relationship between epilepsy and neurodegenerative processes, were furthermore discussed in the scientific commentary by Tai and Galovic (3). Firstly, epileptic seizures might appear earlier in the dementia stages, and therefore before the objective changes in CSF or neuroimaging, a hypothesis supported by the fact that synaptic hyperexcitability develops in the soluble amyloid-β accumulation phase, according to experimental data. The follow-up of the study had a mean of 1.8 years and a longer follow-up may provide more information. The second explanation is related to the possibility of other mechanisms responsible for late-onset epilepsies. Lastly, the authors commented how the results of this study further highlight the complexity of neurodegeneration in epilepsy and closed with one relevant question: how to identify LO-TLE individuals at risk of developing Alzheimer’s disease? A third hypothesis proposes the higher susceptibility of inhibitory interneurons to neurotoxic insults (like hypoxia, deposits of neurotoxic proteins, etc.) compared to excitatory neurons leading to a state of  hyperexcitability and disinhibition of neuronal networks relevant in epileptogenesis (4).
A longitudinal multicenter study published in JAMA Neurology explored the inverse relationship between the two conditions, enrolling 14 685 people with cognitive decline with no epilepsy and investigating which risk factors could be associated with an increased risk of late-onset epilepsy. The authors identified the subsequent factors: APOE4 allele, onset of dementia before the age of 60 years, AD subtype of dementia, increasing severity of dementia, stroke or transient ischemic attack, and Parkinson’s disease(5).

 

Key Points:

  • There is an overlap between late-onset focal epilepsy and Alzheimer’s disease
  • Late onset-temporal lobe epilepsy individuals were found to have normal neurodegenerative biomarkers and no abnormal cortical atrophy pattern
  • The bidirectional relationship between epilepsy and neurodegenerative needs further exploring, in order to identify which patients are going to develop cognitive impairment

References:

  1. Vivash L, Johns H, Churilov L, et al. Phase II randomised placebo-controlled trial of sodium selenate as a disease-modifying treatment in chronic drug-resistant temporal lobe epilepsy: The SeLECT study protocol. BMJ Open. 2023;13:e075888.
  2. Ballerini A, Biagioli N, Carbone C, Chiari A, Tondelli M, Vinceti G, Bedin R, Malagoli M, Genovese M, Scolastico S, Giovannini G, Pugnaghi M, Orlandi N, Lemieux L, Meletti S, Zamboni G, Vaudano AE. Late-onset temporal lobe epilepsy: insights from brain atrophy and Alzheimer's disease biomarkers. Brain. 2024 Jun 25:awae207. doi: 10.1093/brain/awae207. Epub ahead of print. PMID: 38915268.
  3. Tai XY, Galovic M. Late-onset epilepsy and neurodegeneration: intersecting mechanisms or separate entities? Brain. 2025 Jan 7;148(1):6-8. doi: 10.1093/brain/awae401. PMID: 39774833.
  4. Traga Dias Anastacio H, Matorsin N, Ooi L. Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype? Transl Psychiatry 2022 Jun 22; 12(1): 257. Doi: 10.1038/s41398-022-02024-7. PMID: 35732622. PMCID: PMC9217953.
  5. Zawar I, Quigg M, Johnson EL, Ghosal S, Manning C, Kapur J. Risk Factors Associated With Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment. JAMA Neurol. 2025 Jun 1;82(6):605-613. doi: 10.1001/jamaneurol.2025.0552. PMID: 40227723; PMCID: PMC11997859.

Publish on behalf of the Scientific Panel Epilepsy

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