Type 2 diabetes mellitus (DM) accelerates brain aging and increases the risk for dementia and Alzheimer's disease (AD). Currently, there is no treatment for DM-related cognitive decline. Recently, intranasal insulin (INI) therapy has emerged as a potential new solution to deliver insulin safely to the brain and treat DM- related cognitive impairment. Our pilot study showed that a single INI dose of 40IU improved specific cognitive domains and functional connectivity in type 2 DM adults and healthy controls. Previous studies showed that short-term INI treatment is safe and may improve memory in non-diabetic people with cognitive impairment and AD. These studies provided proof-of-concept supporting the potential usefulness and safety of INI; and lay the ground work to determine the long-term effects and safety of prolonged treatment with INI in diabetic population. We propose the following Aims: Aim 1: We propose a randomized, double-blind, placebo-controlled study in 200 older adults with type 2 DM and 200 non-diabetic controls examining whether 40 IU INI once daily over a 24 week period improves: a. specific domains of visuospatial attention and memory, verbal learning (primary outcomes); b. gait speed during a dual task ( as a predictor of overall health), daily living functioning and depression as compared to the DM group receiving sterile saline and the non-diabetic groups. The non-DM groups will provide reference of INI effects in a clinical phenotype of cognitive decline and insulin resistance that occurs with normal aging. Aim 2: We will determine a phenotype predicting a clinically relevant positive response to INI therapy and identify long-term trajectories of INI effects on learning and memory in the DM group vs. the placebo and the non-DM groups. Clinically relevant predictors will be determined based on associations between cognitive function and gait and demographic, glycemic control, insulin resistance, endothelial function and genetic (ApoE4) measures. The trajectory of cognitive, gait dual task and functional performances will be assessed during the 24 weeks of therapy and at 6 months post-treatment. MRI substudy will explore long-term effects on perfusion and resting state functional connectivity and their relationships to cognitive outcomes. Aim 3: To determine the long-term safety of intranasal insulin vs. placebo with regard to glycemic control (fasting glucose, Hb1Ac, hypoglycemic episodes) and vital signs and body mass. This study will help us to determine the safety of prolonged INI treatment; the best outcome domains; and the best patient characteristics to be used in future large-scale efficacy studies. The clinical phenotype and time course predicting optimal response to INI therapy would make it possible to target INI treatment for maximal benefits for preserving cognitive function in older diabetic adults.