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Cited by 61Dementia and Cognitive Impairment ResearchEpilepsy research and treatmentNeurological Disease Mechanisms and Treatments

Association of dementia risk with focal epilepsy and modifiable cardiovascular risk factors

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Tai, Xin You, Torzillo, Emma, Lyall, Donald M., Manohar, Sanjay, Husain, Masud, Sen, Arjune·2023·JAMA Neurology
DOI 10.1001/jamaneurol.2023.0339PMC PMC10043806
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Abstract

Importance: Epilepsy has been associated with cognitive impairment and potentially dementia in older individuals. However, the extent to which epilepsy may increase dementia risk, how this compares with other neurological conditions, and how modifiable cardiovascular risk factors may affect this risk remain unclear. Objective: To compare the differential risks of subsequent dementia for focal epilepsy compared with stroke and migraine as well as healthy controls, stratified by cardiovascular risk. Design, Setting, and Participants: This cross-sectional study is based on data from the UK Biobank, a population-based cohort of more than 500 000 participants aged 38 to 72 years who underwent physiological measurements and cognitive testing and provided biological samples at 1 of 22 centers across the United Kingdom. Participants were eligible for this study if they were without dementia at baseline and had clinical data pertaining to a history of focal epilepsy, stroke, or migraine. The baseline assessment was performed from 2006 to 2010, and participants were followed up until 2021. Exposures: Mutually exclusive groups of participants with epilepsy, stroke, and migraine at baseline assessment and controls (who had none of these conditions). Individuals were divided into low, moderate, or high cardiovascular risk groups based on factors that included waist to hip ratio, history of hypertension, hypercholesterolemia, diabetes, and smoking pack-years. Main Outcomes and Measures: Incident all-cause dementia; measures of executive function; and brain total hippocampal, gray matter, and white matter hyperintensity volumes. Results: Of 495 149 participants (225 481 [45.5%] men; mean [SD] age, 57.5 [8.1] years), 3864 had a diagnosis of focal epilepsy only, 6397 had a history of stroke only, and 14 518 had migraine only. Executive function was comparable between participants with epilepsy and stroke and worse than the control and migraine group. Focal epilepsy was associated with a higher risk of developing dementia (hazard ratio [HR], 4.02; 95% CI, 3.45 to 4.68; P < .001), compared with stroke (HR, 2.56; 95% CI, 2.28 to 2.87; P < .001), or migraine (HR, 1.02; 95% CI, 0.85 to 1.21; P = .94). Participants with focal epilepsy and high cardiovascular risk were more than 13 times more likely to develop dementia (HR, 13.66; 95% CI, 10.61 to 17.60; P < .001) compared with controls with low cardiovascular risk. The imaging subsample included 42 353 participants. Focal epilepsy was associated with lower hippocampal volume (mean difference, −0.17; 95% CI, −0.02 to −0.32; t = −2.18; P = .03) and lower total gray matter volume (mean difference, −0.33; 95% CI, −0.18 to −0.48; t = −4.29; P < .001) compared with controls. There was no significant difference in white matter hyperintensity volume (mean difference, 0.10; 95% CI, −0.07 to 0.26; t = 1.14; P = .26). Conclusions and Relevance: In this study, focal epilepsy was associated with a significant risk of developing dementia, to a greater extent than stroke, which was magnified substantially in individuals with high cardiovascular risk. Further findings suggest that targeting modifiable cardiovascular risk factors may be an effective intervention to reduce dementia risk in individuals with epilepsy.

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  • A strong link between APOE4 and seizure risk has been well established.

    “A strong link between APOE4 and seizure risk has been well established (Sen et al., 2018; Tai et al., 2023; Vossel et al., 2017)”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Tai et al., 2023

    The Methods (Statistical Analysis) and Results (Sensitivity Analysis; page unavailable) use APOE e4 status to assess or control for dementia risk in people with epilepsy. Neither passage addresses whether APOE4 is associated with seizure risk. Searches for APOE e4 with seizure and epilepsy risk found no such finding in our copy. (LLM, conf=0.76)

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Authors
Tai, X. Y., Torzillo, E., Lyall, D. M., Manohar, S., Husain, M., & Sen, A.
Affiliations
  • John Radcliffe Hospital (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
  • University of Glasgow (GB)
  • Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
Corresponding author
Tai, Xin You
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2023-05-01
Volume
80
Issue
5
Pages
445
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2023.0339
PMC
PMC10043806
OpenAlex
W4361000277
Cited by
61
References
3
Citations by year
2026: 21 · 2025: 25 · 2024: 8 · 2023: 7
FWCI
11.74
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, other-oa)
Funders
  • Wellcome Trust
  • National Institute for Health and Care Research
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
focal epilepsy, dementia risk, cardiovascular risk factors, stroke, migraine, executive function, white matter hyperintensities, hippocampal volume, gray matter volume, brain atrophy, cognitive impairment, older adults, hypertension, diabetes mellitus, hypercholesterolemia, smoking, waist-to-hip ratio, UK Biobank, incident dementia, neurodegeneration, neuroinflammation
MeSH terms
Heart Disease Risk Factors, Aged, Cardiovascular Diseases, Cross-Sectional Studies, Dementia, Epilepsy, Epilepsies, Partial, Female, Humans, Male, Middle Aged, Migraine Disorders, Risk Factors, Stroke

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