ObjectiveTo determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.MethodsCross-sectional data, including cerebrospinal fluid (CSF) analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound-B (PiB), magnetic resonance imaging (MRI)-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals of 18–101 years, were analyzed. The age at which each marker exhibited an accelerated change (called the change-point) was estimated, and compared across the markers.ResultsAccelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change-point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change-point at about 60 years, similar to those for MRI hippocampal volume and cortical thickness. The change-point for a cognitive composite occurred at 62.41 years. The change-points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.ConclusionsOur findings support the hypothesized early changes of amyloid in preclinical AD, and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.