Abstract Body: Background: Plasma proteins associated with Alzheimer’s disease (AD) include β-amyloid-42 (Aβ₄₂), phosphorylated -tau at threonine-181 (p-tau₁₈₁), and neurofilament light chain (NfL). This study assessed the relationship between these biomarkers and digital neuropsychological test performance. Methods: Middle-aged participants in the DECADE study had blood drawn and completed the Rowan Digital Cancellation Test (RDCT) consisting of 64 targets embedded among foils. Within 90 seconds, participants circled as many targets as possible, alternating between letters and symbols. RDCT outcomes included correct targets; ‘think’time between correct targets; ‘ink’ time to circle correct targets; total pen strokes; commission errors; and total pen stroke distance and were summarized using factor analysis. Their association with AD biomarkers was done using linear regression. Results: The first 77 participants (age=55.3±8.7; 81.6% female) were included, with serum Aβ₄₂ (mean±SD: 7.8+2.7 pg/ml), p-Tau₁₈₁ (17.2+11.1 pg/ml), and NfL (10.5+13.8 pg/ml) assessed. Factor analysis identified 2 factors (Table). Higher scores on Factor 1 (49.2% variance) correspond to fewer correct responses, more think time, commission errors, and pen strokes. Higher scores on Factor 2 (27.9% variance) correspond to more correct responses, fewer commission errors, ink time, and pen strokes. Adjusting for age, sex, education, and both RDCT factor scores, NfL was negatively associated with Factor 2 (R²= 0.176, β= -0.445[JW1] , SE=2.57; p< 0.01) suggesting worse RDCT test performance with increasing biomarker level. In contrast, Aβ42 was positively associated with Factor 1 (R²=0.268, β= 0.503, SE= p< 0.003. Analyses involving p-Tau₁₈₁ were not significant. Conclusion: In this community-dwelling, middle-aged sample, plasma levels of AD-related proteins are associated with digital measures of neurocognitive performance. Middle-age assessment of serum AD-related proteins and digital neuropsychological performance have the potential to help identify emergent neurodegenerative illness.