BACKGROUND AND OBJECTIVES
Late-onset unexplained epilepsy (LOUE) has been linked to accelerated cognitive decline. However, the role of neurodegenerative proteins and whether they exert their effects through sleep-related mechanisms remain unexplored in this population. The goal of this study was to investigate the association of plasma p-tau217, a measure of Alzheimer disease (AD) pathology, with cognition in LOUE and its association with sleep.
METHODS
Participants with LOUE, with new-onset unprovoked seizures, age at onset 55 years or older, and absence of cortical lesions on MRI, were prospectively recruited. They underwent cognitive testing which included the extended Preclinical Alzheimer Cognitive Composite (PACC5). A 24-hour EEG was obtained, and sleep manually scored. Measures of sleep macroarchitecture and N2/N3 microarchitecture were extracted including slow oscillation (SO), fast spindle (FS), slow spindle (SS), and spindle-SO coupling measures.
RESULTS
Eighty-five participants enrolled (mean age 71.3 ± 7.1 years; 49% female). The average PACC5 Z score (±SD) was -0.63 ± 1.0. Higher plasma levels of log-transformed p-tau217 (per 1 unit increase) were associated with poorer cognition, PACC5 (β = -0.66; 95% CI -1.19 to -0.13; p = 0.0017), after adjusting for age, sex, and education. The severity of epilepsy modulated this relationship: individuals with both elevated p-tau217 and medication-refractory epilepsy exhibited worse cognitive performance (refractory epilepsy * p-tau217 interaction term β = -1.49; 95% CI -2.94 to -0.05; p = 0.04). Higher plasma p-tau217 levels were associated with reduced spindle-SO coupling. Mediation analysis indicated that approximately 24% of the association between p-tau217 and cognition was accounted for by spindle-SO coupling (95% CI 3%-85%, p = 0.032).
DISCUSSION
In individuals with LOUE, elevated plasma p-tau217 was associated with both cognitive impairment and disrupted sleep microarchitecture, with the most pronounced cognitive deficits observed in individuals with medication refractory epilepsy. These findings support the utility of plasma p-tau217 as a biomarker in this population and underscore the role of sleep processes in the relationship between neurodegenerative pathology and cognition in older adults with epilepsy.
R. Sarkis, Hyun-Sik Yang, Lei Liu et al.· Neurology· 0 citations
Importance
Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed.
Objective
To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults.
Design, Setting, and Participants
Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025.
Exposure
Baseline plasma p-tau217.
Main Outcomes and Measures
The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores ≥0.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance).
Results
Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including β-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (>2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/y (95% CI, -0.10 to -0.05), relative to 0.03 units/y (95% CI, 0.02-0.04) in the low p-tau217 group.
Conclusions and Relevance
In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.
R. Buckley, D. Townsend, C. Birkenbihl et al.· Journal of the American Medi...· 1 citation
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