OBJECTIVE To elucidate the relationship between the 2 hallmark proteins of Alzheimer disease (AD), amyloid-β (Aβ) and tau, and clinical decline over time among cognitively normal older individuals. DESIGN A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments. SETTING Research centers across the United States and Canada. PATIENTS We examined 107 participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination. MAIN OUTCOME MEASURES Using linear mixed effects models, we investigated the relationship between cerebrospinal fluid (CSF) phospho-tau 181(p-tau181p), CSF Aβ1-42, and clinical decline as assessed using longitudinal change in global CDR, CDR–Sum of Boxes, and the Alzheimer Disease Assessment Scale–cognitive subscale. RESULTS We found a significant relationship between decreased CSF Aβ1-42 and longitudinal change in global CDR, CDR–Sum of Boxes, and Alzheimer Disease Assessment Scale–cognitive subscale in individuals with elevated CSF p-tau181p. In the absence of CSF p-tau181p, the effect of CSF Aβ1-42 on longitudinal clinical decline was not significantly different from 0. CONCLUSIONS In cognitively normal older individuals, Aβ-associated clinical decline during a mean of 3 years may occur only in the presence of ongoing downstream neurodegeneration.