In patients with late-onset unexplained epilepsy, elevated plasma p-tau217 was associated with both cognitive impairment and disrupted sleep microarchitecture, with approximately 24% of the association between p-tau217 and cognition accounted for by spindle-SO coupling.
Key Findings
Results
Higher plasma p-tau217 levels were associated with poorer cognitive performance in patients with late-onset unexplained epilepsy.
85 participants enrolled with a mean age of 71.3 ± 7.1 years; 49% female
All participants had new-onset unprovoked seizures with age at onset 55 years or older and absence of cortical lesions on MRI
Higher log-transformed p-tau217 (per 1 unit increase) was associated with lower PACC5 scores (β = -0.66; 95% CI -1.19 to -0.13; p = 0.0017)
Association was adjusted for age, sex, and education
The average PACC5 Z score (±SD) was -0.63 ± 1.0, indicating overall below-average cognition in the group
Results
Medication-refractory epilepsy modulated the relationship between p-tau217 and cognition, with the worst cognitive performance in individuals with both elevated p-tau217 and refractory epilepsy.
A statistically significant interaction was found between refractory epilepsy status and p-tau217 on cognitive performance
Refractory epilepsy * p-tau217 interaction term β = -1.49; 95% CI -2.94 to -0.05; p = 0.04
The most pronounced cognitive deficits were observed in individuals with medication-refractory epilepsy and elevated p-tau217
Results
Higher plasma p-tau217 levels were associated with reduced spindle-slow oscillation (SO) coupling during sleep.
A 24-hour EEG was obtained and sleep manually scored for all participants
Sleep measures extracted included slow oscillation (SO), fast spindle (FS), slow spindle (SS), and spindle-SO coupling measures from N2/N3 sleep microarchitecture
Elevated p-tau217 was specifically associated with disrupted spindle-SO coupling, a marker of sleep microarchitecture integrity
Results
Spindle-SO coupling mediated approximately 24% of the association between plasma p-tau217 and cognitive performance.
Mediation analysis indicated that approximately 24% of the association between p-tau217 and cognition was accounted for by spindle-SO coupling
The mediation effect was statistically significant (95% CI 3%–85%, p = 0.032)
The wide confidence interval (3%–85%) reflects uncertainty in the precise magnitude of mediation
Methods
Plasma p-tau217 was used as a measure of Alzheimer disease pathology in a prospectively recruited cohort of late-onset unexplained epilepsy patients.
Participants were prospectively recruited and underwent cognitive testing including the extended Preclinical Alzheimer Cognitive Composite (PACC5)
Inclusion criteria required new-onset unprovoked seizures with age at onset ≥55 years and absence of cortical lesions on MRI
The study design was intended to investigate whether neurodegenerative proteins exert their effects on cognition through sleep-related mechanisms in this population
What This Means
This research suggests that in older adults who develop epilepsy without a clear cause (called late-onset unexplained epilepsy), higher blood levels of a protein called p-tau217 — a marker of Alzheimer's disease pathology — are linked to worse memory and thinking abilities. The study followed 85 adults averaging 71 years old, all of whom had new seizures starting after age 55 with no structural brain lesion to explain them. Participants underwent cognitive testing and had their brain activity and sleep monitored over 24 hours. Those with higher p-tau217 performed worse on cognitive tests, and this effect was even more pronounced in people whose epilepsy did not respond well to medications.
The study also found that higher p-tau217 was associated with disrupted sleep patterns — specifically, a breakdown in the coordination between two types of brain activity during deep sleep called 'spindles' and 'slow oscillations.' This coupling of sleep activity is thought to be important for memory consolidation. Statistical analysis showed that this disrupted sleep coordination accounted for roughly 24% of the link between p-tau217 and poorer cognition, suggesting that sleep disruption may be one pathway through which Alzheimer's-related brain changes harm thinking and memory in people with epilepsy.
This research suggests that measuring p-tau217 in the blood could be a useful tool for identifying older epilepsy patients at greater risk of cognitive decline, and that sleep processes may play a meaningful role in how Alzheimer's pathology affects the brain in this population. The findings highlight that late-onset unexplained epilepsy may intersect with early Alzheimer's disease processes, and that both epilepsy severity and sleep health may be important factors in understanding and potentially addressing cognitive outcomes in these patients.
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Sarkis R, Yang H, Liu L, Lam A, Pavlova M, Lemus H, et al.. (2026). Association Between Alzheimer Pathology, Sleep, and Cognition in Patients With Late-Onset Unexplained Epilepsy.. Neurology. https://doi.org/10.1212/WNL.0000000000218476