AbstractBackgroundTo determine if 3‐year changes in serum insulin resistance (IR) were related to changes in brain volume and glucose uptake, cognition, and CSF biomarkers in cognitively unimpaired and impaired older adults.MethodAlzheimer’s Disease Neuroimaging Initiative data was downloaded for 275 aged adults (55‐89 years). Participants had longitudinal T1‐ and T2‐weighted volume scans, fluorodeoxyglucose (FDG) scans, CSF β‐amyloid (Aβ) and tau species, and cognitive performance over baseline and months 6, 12, 18, 24, and 36. Growth curve modeling in R regressed IR against these outcomes, by itself and with clinical diagnosis as a moderator. Cognitively unimpaired (CU) adults were used as a reference group to determine potential effects in pathological aging.ResultIn AD and/or Mild Cognitive Impairment progressors to AD (MCI‐P), higher IR over time was related to progressive atrophy in medial temporal frontoinsular areas. Similarly, decline was seen in global cognition and both memory and executive function. HOMA1‐IR associations were partially mediated by p‐tau‐181. Among clinical diagnosis groups, higher IR was significantly related to amyloid, p‐tau‐181, and total tau 181 among AD patients but not MCI or unimpaired groups.ConclusionThese findings suggest that in older adults who develop AD or had AD at baseline, higher IR over time is related to brain atrophy and consequent cognitive decline, perhaps as a function of amyloid or tau deposition.