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

摘要 大约25%的65岁以上的美国人患有糖尿病（约1200万人），其中90%以上是2型糖尿病，预计患病率将增加。患有2型糖尿病的老年人患阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD）的风险高出50-100%，但目前仍不清楚如何最好地减轻这种风险。从公共卫生的角度来看，它是必要的，以评估潜在的风险和保护因素，AD/ADRD在这个脆弱的人群。有一些证据表明血糖控制和糖尿病治疗在AD/ADRD风险中起作用，但需要在自然环境中进行研究，以确定与AD/ADRD风险升高相关的长期血糖控制的时变特征，并考虑重要的背景因素，如合并症和糖尿病药物治疗。我们的长期目标是确定2型糖尿病患者中AD/ADRD风险的可改变的风险因素，并帮助提供干预措施和临床实践，旨在改善这一高危人群的健康大脑老化。我们建议创新使用Kaiser Permanente北方加州糖尿病登记处，包括1994-2018年收集的115，000多名2型糖尿病老年人的数据，以更好地了解血糖控制和糖尿病药物治疗对AD/ADRD风险的作用。该提案的具体目的是：1）确定长期血糖控制与大型2型糖尿病老年人队列中AD/ADRD风险之间的纵向关联，并确定哪些模式对AD/ADRD风险最具保护性或有害性; 2）了解微血管和大血管并发症与长期血糖控制对AD/ADRD风险之间的时间依赖性相互作用;和3）评价抗高血糖治疗（例如磺脲类、二甲双胍、噻唑烷二酮类、胰岛素）与AD/ADRD风险之间的相关性，同时考虑长期血糖控制。该提案的结果将直接为老年糖尿病患者的治疗目标和治疗管理提供信息，老年糖尿病患者在AD/ADRD高风险老年人群中的比例越来越大。

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.