BACKGROUND:Intranasally administered insulin has shown promise in both rodent and human studies in Alzheimer’s disease; however, both effects and mechanisms require elucidation.OBJECTIVE:We assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer’s disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909).DESIGN:A randomized (1:1) double-blind clinical trial.SETTING:Twelve sites across the United States.PARTICIPANTS:Adults with mild cognitive impairment or Alzheimer’s disease.INTERVENTION:Participants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled.MEASUREMENTS:Changes from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer’s Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite.RESULTS:The insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer’s disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group.Conclusion:Intranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin’s potential as a therapeutic option for Alzheimer’s disease.