Objective. The amyloid/tau/neurodegeneration (ATN) research framework for Alzheimer’s disease (AD) was proposed to organize AD biomarkers and to stage AD across its preclinical and symptomatic phases. Applying this framework requires a large number of participants since the framework envisions eight biomarker profiles. This study examined the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct ATN profiles. Methods. Pooling data across four cohort studies, 814 cognitively normal participants (mean baseline age=59·6 years) were classified into eight ATN groups using baseline CSF levels of Aβ1-42 as a measure of amyloid (A), phosphorylated tau 181 (p-tau181) as a measure of tau (T), and total tau (t-tau) as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination (MMSE). We compare the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years). Results. Using different model formulations and cut-points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A-T-N-). Replicating prior findings using the 2011 NIA-AA/SNAP schema, only individuals with abnormal levels of both amyloid and p-tau181 or t-tau (Stage 2) showed greater cognitive decline than those with normal biomarker levels (Stage 0). Conclusions. The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.