P3‐455: A randomized, placebo‐controlled trial of intranasal insulin in amnestic MCI and early Alzheimer's

Abstract

Alzheimer's disease (AD) is associated with plasma insulin elevations and insulin resistance, which may down-regulate transport of insulin to the brain and influence Aβ regulation, glucose metabolism, and other mechanisms related to disease pathogenesis. Reduced insulin signaling and low CSF-to-plasma insulin ratios have been observed in AD. Furthermore, intravenous insulin administration (while maintaining euglycemia) improves memory, possibly by augmenting low brain levels. Peripherally administered insulin is not a viable treatment due to the risk of hypoglycemia. However, with intranasal administration, insulin follows extracellular pathways to the brain, bypassing the periphery. Direct access to the CNS occurs within 15 minutes without risk of hypoglycemia. We have demonstrated previously that cognition is enhanced acutely following a single dose of intranasal insulin as well as following 21-day twice-daily dosing in adults with amnestic mild cognitive impairment (MCI) and early AD. Participants (n = 107; 65 MCI, mean age = 72.2, mean 3MSE = 92.10; 42 AD, mean age = 73.6, mean 3MSE = 70.0) were randomized to receive either placebo, or 10 or 20 IU bid intranasal insulin treatment using an electronic atomizer (Kurve Technology) for four months. The ADAS-Cog/MCI and story recall were the primary outcome measures. These tests were administered at baseline, at 2 and 4 months during treatment, and 2 months after treatment cessation. Additional cognitive testing, functional measures, and mood measures were also administered. A subset of participants received FDG-PET and/or lumbar punctures at baseline and after 4 months of treatment. Enrollment has been completed, and all data collection will be finished by March 1, 2010. Preliminary analyses of a subset of participants (n = 19) who received LPs showed a trend for an improved AD CSF biomarker profile (increased Aβ42/tau ratio, p = 0.07). Similarly, initial inspection of a subset of FDG-PET images revealed improved cerebral glucose metabolism for 3 participants treated with the 20 IU dose, and no change for 3 placebo-assigned participants. Data from the full sample will be presented to determine whether these promising trends are strengthened, and whether positive effects are observed for the primary and secondary outcome measures. These results will provide critical information regarding the potential therapeutic benefits of intranasal administration for patients with MCI and AD.