RESTING-STATE EEG SIGNATURES OF ABNORMAL COGNITION AND PLASMA MARKERS OF PATHOLOGICAL AGING IN MIDDLE-AGED ADULTS

Alterations across behavioral, molecular, and neurophysiological domains may precede pathological cognitive decline before symptoms, making early identification of subtle vulnerability critical for prevention. Neuropsychological testing, plasma biomarkers, and resting-state EEG (rsEEG) are candidates for early detection. We examined convergence across these dimensions in healthy middle-aged participants from the Barcelona Brain Health Initiative (n=126; mean age=53.9±7.1 years; 45% women), identifying outliers using the interquartile range method (values <Q1−1.5×IQR or >Q3+1.5×IQR). All cognitive outliers showed low performance, while all plasma outliers showed elevated biomarker levels. Participants underwent 64-channel rsEEG during eyes-closed (EC) and eyes-open (EO), neuropsychological assessment, and plasma quantification of neurofilament light chain (NfL) and phosphorylated tau-181 (p-tau181). From rsEEG we derived global-mean spectral parameterization, connectivity, microstates, and entropy measures. We identified 5 cognitive and 8 plasma outliers. In EC, 80% of cognitive and 75% of plasma outliers were also classified as rsEEG outliers across multiple measure domains. Convergence was lower in EO (20% cognitive; 50% plasma). Cognitive outliers showed elevated entropy values, while plasma outliers exhibited atypical microstate prototype amplitudes. Spectrally, p-tau181 outliers showed elevated delta/theta relative power, whereas NfL outliers exhibited elevated alpha relative power. EC captured convergence for both biomarkers, while EO detected only NfL-related patterns. The single non-convergent plasma outlier had elevated but sub-pathological levels, whereas all convergent cases showed pathological concentrations. Together, these findings suggest that rsEEG, particularly in EC condition, may reflect neurophysiological alterations associated with cognitive and plasma biomarker outlier profiles in otherwise healthy individuals.