Application of the AT(N) Framework in Older Adults with Epilepsy: Plasma Biomarkers and Associations with Demographic, Seizure, and Cognitive Variables
Abstract number :
3.166
Submission category :
2. Translational Research / 2C. Biomarkers
Year :
2025
Submission ID :
886
Source :
www.aesnet.org
Presentation date :
12/8/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Kayela Arrotta, PhD – Cleveland Clinic
Katherine Bangen, PhD – UCSD
Anny Reyes, PhD – Cleveland Clinic
Natalia Mendez, BS – University of California at San Diego
Lisa Ferguson, MA – Cleveland Clinic
Dace Almane, MS – University of Wisconsin-Madison
Jana Jones, PhD – University of Wisconsin–Madison
Bruce Hermann, PhD – University of Wisconsin-Madison
Robyn Busch, PhD – Cleveland Clinic
Carrie McDonald, PhD – University of California, San Diego
Rationale: The National Institute on Aging and Alzheimer's Association (NIA-AA) research framework on Alzheimer's disease (AD) uses a three-biomarker construct: Aß-amyloid (A), tau (T) and neurodegeneration [(N)] to classify AD pathological change in the aging population. Emerging evidence suggests these biomarkers may also have diagnostic and prognostic value in epilepsy. Amyloid burden has been linked to late-onset epilepsy and cognitive impairment, tau pathology may relate to seizure susceptibility and severity, and neurofilament light chain (NfL, a plasma marker of neurodegeneration), has been associated with cognitive dysfunction and status epilepticus. This study applied the AT(N) framework to older adults with epilepsy to examine biomarker prevalence and associations with demographic, seizure, and cognitive characteristics.
Methods: As part of the Brain Aging and Cognition in Epilepsy (BrACE) study, 80 older adults with focal epilepsy (Mean age = 66.5 years; range: 55–84) were classified as A+, T+, and/or (N)+ based on plasma Aβ42/Aβ40 ratio, p-tau181, and NfL levels, respectively. Participants were grouped into three AT(N) categories: normal biomarkers, AD continuum pathology, and non-AD pathology. Demographic and seizure characteristics (age, sex, ethnicity, race, education, age at epilepsy onset, epilepsy duration, refractory status, history of status epilepticus, and side/site of focal epilepsy) were compared across groups using ANOVA/Kruskal-Wallis tests and Fisher’s exact tests. Cognitive status was determined using IC-CoDE (International Classification of Cognitive Disorders in Epilepsy; intact vs. impaired) and Montreal Cognitive Assessment (MoCA) total score. Associations between AT(N) profiles and cognition were analyzed using logistic and linear regression.
Results: 31% of participants had normal biomarkers, 38% fell within the AD-continuum, and 31% showed non-AD pathology (Figure 1). Participants with normal biomarkers were significantly younger (p = 0.030); no other demographic or seizure-related variables differed by AT(N) profile. While categorical AT(N) groups were not associated with cognitive status, post-hoc analyses using continuous biomarker values revealed that greater amyloid burden was significantly associated with lower MoCA scores (β = 0.97, 95% CI: 0.02–1.91, p = 0.050).
Conclusions: Older adults with epilepsy showed a relatively even distribution across AT(N) biomarker categories, suggesting heterogeneity in underlying AD pathology. Compared to typical aging trends, individuals with epilepsy appear to have lower rates of normal biomarkers. Among demographic, seizure, and cognitive variables, only age was associated with AT(N) classification. However, secondary analysis demonstrated that elevated amyloid burden was independently linked to lower global cognitive performance. These findings suggest AD-related biomarkers may have relevance in epilepsy, and follow-up studies are underway to examine their association with progressive cognitive course, particularly in relation to memory.
Funding: This research was supported by the National Institutes of Health R01NS120976 and the Cleveland Clinic Epilepsy Center.
Translational Research