Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment A Pilot Clinical Trial

Objective: To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Design: Randomized, double-blind, placebo-controlled trial. Setting: Clinical research unit of a Veterans Affairs medical center. Participants: The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n=64) or mild to moderate AD (n=40). Intervention: Participants received placebo (n=30), 20 IU of insulin (n=36), or 40 IU of insulin (n=38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Main Outcome Measures: Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n=23) and positron emission tomography with fludeoxyglucose F 18 (n=40) before and after treatment. Results: Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayedmemory(P <.05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P <.01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P <.05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the A beta 42 level and in the tau protein-to-A beta 42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred. Conclusions: These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD.