Abstract
INTRODUCTION: The locus coeruleus is among the earliest brain regions affected by tau pathology in Alzheimer's disease (AD), but the functional impact is difficult to measure in vivo. Task-evoked pupil dilation provides an index of locus coeruleus-norepinephrine function that might be altered in cognitively normal older adults with underlying AD pathology. METHODS: Cognitively normal older adults identified as AD biomarker positive (N = 25) or negative (N = 36) based on plasma phosphorylated tau (p-tau) levels completed a conjunctive visual search task that manipulated attentional load by varying set size. Pupil dilation responses during the task were analyzed using mixed-effects models and time-resolved regression. RESULTS: Despite comparable accuracy and reaction times, biomarker-positive adults showed reduced load-dependent modulation of pupil dilation during target-present trials. Weaker modulation was associated with higher p-tau levels and poorer executive and memory function. DISCUSSION: Attenuated task-evoked modulation of pupil dilation during visual search reveals locus coeruleus-norepinephrine dysfunction in preclinical AD.