Vascular Risk Factors and Late-Onset Epilepsy

Late-onset epilepsy (LOE; onset at age ≥65 years) is increasingly recognized in older adults and may be associated with vascular risk.

To identify vascular risk factors (VRFs) associated with incident LOE in older adults.

This study is an individual participant data meta-analysis of 6 US population-based prospective cohort studies (the Epilepsy-Cog Study). In 5 cohorts linked to Medicare for epilepsy case ascertainment, follow-up for LOE began when a participant had accrued 2 years of continuous fee-for-service enrollment and was 65 years of age or older and extended to the end of continuous enrollment. Claims linkage covered 1991-2018 in the Atherosclerosis Risk in Communities Study (ARIC), 1992-2019 in the Cardiovascular Health Study (CHS), 2000-2019 in the Multi-Ethnic Study of Atherosclerosis (MESA), 2000-2020 in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS), and 1999-2019 in the Washington Heights/Inwood Columbia Aging Project (WHICAP). In the Northern Manhattan Study (NOMAS), which was not Medicare linked and used cohort-based epilepsy case ascertainment, follow-up for LOE began at cohort entry in 1993-2008 and extended to 2024. Data analysis was completed in January 2026.

Sociodemographic characteristics and VRFs assessed by self-report, examinations, laboratory measures, and medication use.

The primary outcome was incident LOE. Associations between risk factors and incident LOE were evaluated using multivariable Cox proportional hazards models to estimate hazard ratios.

From 43 753 participants in Epilepsy-Cog, 551 participants with prevalent epilepsy and 945 with no follow-up after Epilepsy-Cog baseline were excluded. Among 42 257 participants (mean [SD] age, 71.4 [6.9] years; 23 383 [56.0%] female) followed up for a mean (SD) of 9.3 (6.2) years, 1500 participants (3.5%) developed LOE (3.8 per 1000 person-years). In fully adjusted models, LOE risk was higher with current smoking (HR = 1.39; 95% CI, 1.18-1.64), hypertension (HR = 1.17; 95% CI, 1.04-1.31), diabetes (HR = 1.42; 95% CI, 1.25-1.62), chronic kidney disease (HR = 1.29; 95% CI, 1.13-1.48), history of stroke (HR = 1.99; 95% CI, 1.63-2.43), and apolipoprotein E ε4 allele (1 ε4 allele: HR = 1.22; 95% CI, 1.07-1.39; 2 ε4 alleles: HR = 1.84; 95% CI, 1.36-2.50). Associations of VRFs with LOE were similar across age, sex, and race and ethnicity subgroups.

In this pooled analysis of 6 US cohorts, multiple VRFs and a history of stroke were associated with incident LOE. These findings suggest that LOE may reflect the underlying burden of brain vascular disease.