IMPORTANCE: Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood. OBJECTIVE: To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5). MAINOUTCOMESANDMEASURES: Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus. RESULTS: Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42-positive individuals but not among CSF Aβ1-42-negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau 181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts. CONCLUSIONS AND RELEVANCE: In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss. © Copyright 2014 American Medical Association. All rights reserved.