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Multicenter Study
. 2025 Jun 1;82(6):605-613.
doi: 10.1001/jamaneurol.2025.0552.

Risk Factors Associated With Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment

Ifrah Zawar  1 , Mark Quigg  1   2 , Emily L Johnson  3 , Soutik Ghosal  4 , Carol Manning  5 , Jaideep Kapur  1
Affiliations
Multicenter Study

Risk Factors Associated With Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment

Ifrah Zawar et al. JAMA Neurol. .

Abstract

Importance: The risk of developing epilepsy substantially increases after the age of 60 years (late-onset epilepsy [LOE]), particularly in people with cognitive decline ([PWCD] ie, dementia and/or mild cognitive impairment). Epilepsy is associated with worse cognitive and mortality outcomes in PWCD. Identifying PWCD at risk for developing LOE can facilitate early screening and treatment of epilepsy.

Objective: To investigate factors associated with LOE in PWCD.

Design, setting, and participants: This longitudinal, multicenter study is based on participants from 39 US Alzheimer's Disease Research Centers from September 2005 through December 2021. Of 44 713 participants, 25 119 PWCD were identified. Of these, 14 685 were included who did not have epilepsy at enrollment, had 2 or more visits, and were 60 years or older at the most recent follow-up.

Exposure: The association between various factors and LOE development in PWCD was investigated.

Main outcomes and measures: The primary outcome was LOE, defined as seizures starting at or after 60 years of age. Those who did not develop LOE but were 60 years or older at follow-up served as controls. A multivariable Cox regression analysis assessed the association between various factors and LOE. Independent variables included age, sex, and socioeconomic factors (education, race, ethnicity), cardiovascular risks (hypertension, diabetes, hyperlipidemia), cerebrovascular disease (stroke or history of transient ischemic attack [TIA]), other neurologic comorbidities (Parkinson disease [PD], traumatic brain injury), cognition (age at dementia onset, dementia severity, type of dementia [Alzheimer disease (AD) vs non-AD]), genetics (apolipoprotein E4 [APOE4] status), lifestyle (alcohol misuse, smoking), and depression.

Results: Of the 14 685 participants (7355 female [50%] and 7330 male [50%]; mean [SD] age, 73.8 [8.5] years) who met the inclusion criteria, 221 participants (1.5%) developed LOE during follow-up. After adjusting for demographics, cardiovascular risks, neurologic comorbidities, genetics, cognitive factors, and depression, the following were associated with a higher risk of developing LOE: APOE4 allele (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.04-1.86; P = .03), dementia onset before age 60 years (aHR, 2.46; 95% CI, 1.53-3.95; P < .001), worse cognition (aHR, 2.35; 95% CI, 1.97-2.79; P < .001), AD dementia subtype (aHR, 1.68; 95% CI, 1.13-2.49; P = .01), stroke/TIA (aHR, 2.03; 95% CI, 1.37-3.01; P < .001), and PD (aHR, 2.53; 95% CI, 1.08-5.95; P = .03). In sensitivity analysis, using an alternative LOE definition of epilepsy onset after age 65 years revealed the same factors associated with LOE.

Conclusion and relevance: This study showed that the APOE4 allele, dementia onset before age 60 years, AD dementia subtype, worse cognition, stroke/TIA, and PD are associated with LOE development in PWCD. PWCD with these risk factors may be considered for routine screening with an electroencephalogram for early identification of LOE.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Zawar reported grants from the American Epilepsy Society, the BAND foundation, the Alzheimer’s Association, and the National Institutes of Health during the conduct of the study. Dr Quigg reported grants from the National Institute of Neurological Disorders and Stroke during the conduct of the study. Dr Johnson reported grants from the National Institutes of Health (K23 AG063899) during the conduct of the study. Dr Kapur reported grants from the National Institute of Neurological Disorders and Stroke (5R37NS119012 and5R01NS120945) during the conduct of the study and personal fees from Marinus Pharma and grants from Ovid Therapeutics paid to their institution outside the submitted work. No other disclosures were reported.

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