Abstract The proposed study will examine the therapeutic effects of intranasally-administered insulin in adults with amnestic mild cognitive impairment (aMCI) or mild Alzheimer?s disease (AD). The study rationale is derived from evidence that insulin carries out multiple functions in the brain, and that insulin dysregulation contributes to AD pathogenesis. For example, insulin protects against the synaptotoxic effects of -amyloid and facilitates memory, as well as influencing tau phosphorylation. Low cerebrospinal fluid (CSF) insulin and reduced brain insulin signaling have been described in persons with AD, suggesting that therapies aimed at correcting these deficiencies may be beneficial. One such strategy is normalizing brain insulin levels through intranasal insulin administration (INI). Intranasally-administered insulin travels via bulk flow through extracellular pathways to the brain, bypassing the periphery and leaving peripheral glucose levels unchanged. In a pilot study, INI safely improved delayed memory in persons with AD and aMCI and prevented progressive hypometabolism in the cuneus region as demonstrated with positron emission tomography. Based on these promising results we propose a Phase IIB multi-site, randomized, double-blind trial comparing the effects of INI (20 IU bid) and placebo for 12 months, followed by a 6 month open label period in which all participants will receive active treatment. Intranasal insulin will be administered with the use of an innovative electronic atomizer designed to maximize nose-to-brain transport. Two-hundred and forty participants with aMCI (Petersen criteria, Clinical Dementia Rating/CDR 0.5) or mild AD (NINDS-ADRDA criteria, CDR 0.5-1.0, Mini-mental State Exam?20) will be enrolled. The primary outcome measure will consist of the AD Assessment Scale for Cognition, 12-item version. Secondary measures will include a memory composite, CDR Sum of Boxes, and Functional Activities Questionnaire. Cognitive/functional assessment will occur at 6 month intervals. Hippocampal and entorhinal cortex volume will be measured at baseline and 12 months with magnetic resonance imaging. CSF biomarkers will also be measured then for a subset of participants. For the intent-to-treat efficacy analyses for the primary (ADAS-Cog12) and secondary (memory composite, CDR SB, FAQ) measures, longitudinal scores will be analyzed using random effects models to assess the differences in the rate of change across treatment groups. The 6-month open label period will provide exploratory longer-term safety data and efficacy data, as well as serving as a significant recruitment and retention incentive.The trial will be conducted in collaboration with the AD Cooperative Study Consortium (Paul Aisen, MD, Director) and thus benefit from its wellestablished infrastructure and expertise. We will use the ADCS's comprehensive coordination services as well as its member sites which have extensive AD clinical trial experience. Our results will provide a strong rationale and useful data for the design of a future Phase III trial and generate critical evidence for the efficacy, safety, and mechanistic underpinnings of this novel therapeutic approach.