Prefrontal hemodynamic alterations during resting state and stroop interference in cognitively healthy older adults with high plasma pTau-217 levels

Plasma phosphorylated tau-217 (pTau-217) has emerged as a sensitive biomarker for early Alzheimer's disease (AD) pathology, including the cognitively healthy (CH) stage when compensatory frontal activity has been reported. This study focused on hemodynamic changes measured using functional near-infrared spectroscopy (fNIRS) in the prefrontal cortex (PFC) in CH older adults. The fNIRS data from 41 CH older adults during resting state, as well as during a color-word Stroop interference task were analyzed. Primary measures included oxyhemoglobin (HbO) responses at left lateral, left medium, right medium, and right lateral PFC regions, exploratory measures included heart rate, Weighted Phase Lag Index (wPLI) for functional connectivity (FC), and correlation between HbO and heart rate (HR) to assess heart–brain coupling. The study revealed that compared to low tertile group, individuals with high tertile pTau-217 exhibited slower response times during the task and region-specific hemodynamic changes - reduced HbO during eyes-open rest (FDR-adjusted p = 0.037) but increased activation during Stroop congruent trials (False Discovery Rate (FDR)-adjusted p < 0.0001), which are supported by sensitivity analysis. Additionally, high tertile pTau-217 group showed strong positive correlation between post-task HR and right-lateral prefrontal HbO (ρ = 0.85, p < 0.001) versus a negative correlation in the low tertile group (ρ = −0.55, p = 0.043) and attenuated interhemispheric synchronization by FC (measured by wPLI), particularly during eyes-open resting state. Overall, the primary findings demonstrate pTau-217-associated differences in prefrontal hemodynamic responses, while the exploratory heart–brain coupling and FC findings are hypothesis-generating and require independent validation. Larger and more diverse cohorts are needed to confirm and generalize these findings.