Continued progress in life expectancy is accompanied by the elevated risk of age-related disorders including diabetes and Alzheimer's disease (AD). The current proposal aims to assess cause and effect relationships of combination therapy of insulin and anti-diabetes medications on cognitive impairment and quantitative indices of AD neuropathology (accumulation of soluble and insoluble Amyloid beta peptides and loss of dendritic spines) in cerebral cortex of the AD mouse model. We expect that the outcome of the hypotheses tested will significantly enhance our conceptual framework of the neurobiological mechanisms of cognitive compromise in diabetes and AD, and develop a model-based testbed for therapeutic strategies for elderly patients at risk of type 2 diabetes and AD-associated dementia.