Before It's Too Late: Recognizing the Impact of Seizures and Risk Factors for Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment

Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia Zawar I, Quigg M, Ghosal S, Punia V, Calle-Lopez Y, Manning C, Kapur J. Ann Neurol . 2025;97(2):358–368. doi: 10.1002/ana.27125 . Epub 2024 Oct 30. PMID: 39475168 Objectives: The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact of seizure control on mortality, function, cognition, and mood among PWD. Methods: This longitudinal, multicenter study is based on 39 Alzheimer's disease centers (ADCs) in the United States from September 2005 to December 2021. PWD were grouped by seizure status into recurrent (seizures in the past year), remote (prior seizures but none in the past year), and no seizures (controls). The primary outcome was all-cause mortality among seizure groups. We used Weibull survival analysis to assess the mortality risks by seizure status after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree of cognitive impairment, dominant Alzheimer's disease (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, and depression. Cognition (Clinical Dementia Rating), function (physical dependence and nursing home residence), day-to-day activities (Functional Assessment Scores), and mood (Geriatric Depression Scale) were compared among seizure groups after adjusting for dementia duration and age. Results: Among 26,501 participants, 374 (1.4%) had recurrent seizures and 510 (1.9%) had remote seizures. In multivariable survival analysis, recurrent seizures were associated with a higher mortality risk than remote and no seizures (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; recurrent aHR = 1.79, 95% CI = 1.51 to 2.12; remote aHR = 1.17, 95%CI = 0.98 to 1.38). Median time-to-death for recurrent, remote, and no seizures was 2.4, 4.0, and 4.7 years, respectively. People with recurrent seizures had worse cognition, day-to-day function, and physical dependence than those with remote seizures and controls. Interpretation: PWD with poorly controlled recurrent seizures have worse mortality, functional, and cognitive outcomes than PWD with remote and no seizures. These findings underscore the need for timely identification and management of ongoing seizures in PWD. Risk Factors Associated With Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment Zawar I, Quigg M, Johnson EL, Ghosal S, Manning C, Kapur J. JAMA Neurol . 2025;82(6):605–613. doi: 10.1001/jamaneurol.2025.0552 . PMID: 40227723. 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) versus 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.