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Abstract INTRODUCTION Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR). METHODS We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle (n = 58) and the Consortium for the Early Identification of Alzheimer's Disease‐Quebec (CIMA‐Q; n = 61). We further investigated the brain cellular contribution for sIR using human cell lines. RESULTS CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aβ)42 and Aβ40 levels significantly correlated as well as CSF sIR and cognition in the CIMA‐Q cohort. Human neurons expressing the amyloid precursor protein “Swedish” mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus. DISCUSSION These data support further investigation into the generation and role of sIR in AD. Highlights Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aβ)42 and Aβ40. CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score). CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups. Neurons derived from humans with the “Swedish” mutation in which Aβ42 is increased generate increased levels of sIR. Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin.