Attentionally directed oculomotor training produces disease-stage-dependent effects on plasma tau, cognition, and oculomotor signatures in patients with mild cognitive impairment.

Attentionally directed oculomotor training may engage circuits implicated in gamma-band modulation and early Alzheimer's disease (AD) pathophysiology, yet its effects across mild cognitive impairment (MCI) risk strata remain unclear. We aimed to determine whether this training, delivered through a gamified eye-tracking task, is associated with differential effects on plasma neurodegeneration biomarkers, cognitive performance, and oculomotor signatures in individuals with MCI at differential risk of conversion to Alzheimer's dementia. Twenty-nine participants with MCI were stratified into MCI-HR (n = 17) and MCI-LR (n = 12) based on validated MoCA and MoCA-MIS cut-off scores and completed 8 weeks of daily oculomotor training. Outcomes were assessed pre/post using permutation tests, bootstrapped Hedges' g, and linear mixed-effects models. Cognitive performance improved in both groups (MoCA: g = 1.27-2.17; MoCA-MIS: g = 1.02-1.68), with no between-group difference. Plasma tau diverged by stratum: MCI-LR showed reductions in pTau-181 (g = -0.64, 95% CI [-1.07, -0.15]) and pTau-217 (g = -0.72, 95% CI [-1.08, -0.36]), whereas MCI-HR showed an increase in pTau-181 (g = 0.82, 95% CI [0.53, 1.16]; between-group g = 1.31, 95% CI [0.89, 1.78], p = 0.001). Amyloid, GFAP, and NfL remained stable. MCI-HR showed reduced accuracy and increased reaction times (+196.4 ms, p < 0.001); MCI-LR maintained stable performance. Oculomotor signatures diverged between strata post-training (group × time × stimulus interactions, p = 0.013-0.045). In MCI-LR, oculomotor changes correlated with reductions in pTau-181 (ρ = -0.60, 95% CI [-0.96, -0.20]) and pTau-217 (ρ = -0.69, 95% CI [-0.95, -0.20]). Oculomotor training produced stratum-dependent responses: biomarker reductions and oculomotor-molecular coupling in MCI-LR, and dissociated physiological and behavioral outcomes in MCI-HR, suggesting disease-stage-specific neuroplasticity capacity linked to tau-related processes.