Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer’s Disease

• Published in: The journal of prevention of Alzheimer's disease 2021, Vol.8 (3), p.240-248
• Main Authors: Kellar, D., Lockhart, S. N., Aisen, P., Raman, R., Rissman, R. A., Brewer, J., Craft, Suzanne
• Format: Article
• Language: English
• Subjects: Activities of Daily Living; Administration, Intranasal; Aged; Alzheimer Disease - drug therapy; Biomarkers - cerebrospinal fluid; Brain - physiopathology; Cognition - drug effects; Cognitive Dysfunction - drug therapy; Female; Geriatrics/Gerontology; Humans; Hypoglycemic Agents - therapeutic use; Image Processing, Computer-Assisted - statistics & numerical data; Insulin - therapeutic use; Insulin, Regular, Human - therapeutic use; Magnetic Resonance Imaging; Male; Medicine; Medicine & Public Health; Neurology; Neuropsychological Tests - statistics & numerical data; Original Research; White Matter - pathology
• ISSN: 2274-5807; 2426-0266
• DOI: 10.14283/jpad.2021.14

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.