Cognitive vergence and pupillary responses as functional oculomotor signatures to differentiate AT(N) biological profiles in older adults with mild cognitive impairment

The locus coeruleus (LC), the earliest site of tau accumulation in Alzheimer's disease, directly influences pupillary and vergence oculomotor systems. Whether task-evoked oculomotor dynamics can non-invasively differentiate AT(N) profiles, A+T+ (biological Alzheimer's disease) and A-T+ (suspected non-Alzheimer's tauopathy), remains unexamined despite their differential impact on LC-mediated modulation and cortical network integrity. Thirty-eight MCI individuals (12 A-T+, 26 A+T+), classified using validated CSF biomarker thresholds, completed a visual oddball paradigm under binocular eye-tracking. Linear mixed-effects models examined profile × condition interactions across full time series and six trial-level features; participant-level associations were tested using Firth-penalized logistic regression to account for the small and imbalanced sample. Profiles did not differ in oculomotor magnitude but diverged in temporal organization. Profile × condition interactions were significant for vergence global slope, vergence time to peak, and pupillary time to peak (all p-Holm ≤ 0.048). Timing differences were condition-dependent: A-T+ showed later responses during distractor trials, while A+T+ showed the most delayed timing during target trials. Subject-level associations were significant for vergence and pupillary time to peak, with greater condition-dependent modulation predicting higher A+T+ probability (ORs = 0.43 and 0.35; both p < 0.05); vergence global slope delta did not reach significance at the subject level. A-T+ showed superior target detection accuracy (89.7% vs. 82.5%, p = 0.003). Cognitive vergence and pupillary dynamics showed condition-dependent patterns differentiating AT(N) biological profiles in this MCI sample, supporting portable, low-cost eye-tracking as a non-invasive complement to CSF-based characterization, pending confirmation in larger, independent cohorts.