Background: Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size. Objective: To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid42 (Aβ42), tau, and phosphorylated tau (ptau181) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment. Design: Longitudinal cohort study. Setting: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri. Participants: A convenience sample of 197 individuals 50years and older with normal cognition (ClinicalDementia Rating of 0) at baseline observed for a mean of 3.3 years. Main Outcome Measure: Time to Clinical Dementia Rating ≥ 0.5. Results: Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P=.02) and ptau (P=.008). In those with lower tau values, nWBV (hazard ratio [HR],0.54; 95% confidence interval [CI], 0.31-0.91; P=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P=.02). Conclusion: In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.