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Introduction: We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline., Methods: IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E ε4 allele ( APOE ε4) carrier status predicted amyloid beta [Aβ] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253)., Results: Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x APOE4 was not related to Aβ chronicity but was significantly associated with CSF phosphorylated tau (P-tau) 181 /Aβ 42 level., Discussion: In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)