Glycemic Control and Dementia: The Role of Pharmacotherapy and Vascular Complications

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ABSTRACT Approximately 25% of Americans over the age of 65 are living with diabetes (~12 million individuals), over 90% of which is type 2 diabetes, and the prevalence is expected to increase. Elderly individuals with type 2 diabetes have 50-100% higher risk of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) yet it remains unclear how to best mitigate this risk. From a public health standpoint it is imperative to evaluate potential risk and protective factors for AD/ADRD in this vulnerable population. There is some evidence that glycemic control and diabetes treatments play a role in AD/ADRD risk but studies in natural settings are need to identifying time-varying characteristics of long-term glycemic control associated with elevated AD/ADRD risk into consideration important contextual factors such comorbidities and diabetes pharmacotherapy. Our long-term goal is to identify modifiable risk factors of AD/ADRD risk among individuals with type 2 diabetes and to help inform interventions and clinical practice aimed at improving healthy brain aging among this at-risk population. We propose an innovative use of the Kaiser Permanente Northern California Diabetes Registry encompassing data collected from 1994-2018+ in over 115,000 elderly people with type 2 diabetes to engender a better understanding of the role of glycemic control and diabetes pharmacotherapy on AD/ADRD risk. The specific aims of the proposal are to: 1) Determine the longitudinal association between long-term glycemic control and risk of AD/ADRD in a large cohort of elderly individuals with type 2 diabetes and identify which patterns are most protective or harmful for AD/ADRD risk; 2) Understand the time-dependent interplay between micro- and macrovascular complications and long-term glycemic control on AD/ADRD risk; and 3) Evaluate the association between anti-hyperglycemic therapies (e.g. sulfonylureas, metformin, thiazolidinediones, insulins) and risk of AD/ADRD while accounting for long-term glycemic control. Findings from the proposal will be directly inform treatment targets and therapeutic management of geriatric patients with diabetes, an increasing portion of our elderly population at high risk of AD/ADRD.