Diabetes Treatment for the Prevention of Stroke and Vascular Dementia

Type 2 Diabetes Mellitus (T2DM) is associated with a multitude of secondary complications, including vascular disease, dementia, and stroke. In addition, T2DM confers an increased risk for Alzheimer’s disease (AD), through undetermined, and likely complex, mechanisms. In order to investigate the impact of T2DM on AD pathology, we have created a novel mouse model that recapitulates features of both diseases. Our preliminary data show that these animals have significant vascular pathology, including aneurysms and strokes. In addition, these mice display a significant cognitive deficit, likely arising due to the extensive stroke pathology. Our central hypothesis is that T2DM lowers the threshold for stroke in mice with AD-induced vascular pathology. In order to determine if clinical intervention is sufficient to affect this complication, we propose modifying stroke incidence through anti-diabetes treatment in mid-life. To this end, we will use metformin, the most commonly prescribed diabetes drug, and use MRI to determine the effect on cerebrovascular health: In addition, we plan to test the effect of treatment on cognition using the Morris Water Maze paradigm. The major strength of this proposal is our unique mouse model. We have already created this model and know from preliminary analyses that it exhibits extreme obesity, impaired glucose tolerance, and amyloid pathology. In addition, we know that these mice can be aged >12 months, allowing the study of age-related phenomena, such as stroke and AD. We will significantly add to our previous studies by modifying the outcome through antidiabetes medication. This project has the potential to advance our understanding of the diabetesconferred risk for dementia and could provide a foundation for future therapeutic strategies for T2DM patients with vascular and AD-like dementia.