Glucose Variability as a Digital Biomarker for Preclinical AD Risk in Prediabetes.

项目摘要 需要可靠的数字诊断工具来早期发现认知功能障碍和分层 2型糖尿病(T2 DM)高危老年人的早期阿尔茨海默氏症(AD)风险。T2 DM是一口井- 已知的认知衰退和AD风险的加速器：T2 DM与情景记忆和 执行功能，并使AD的风险增加2到4倍。糖尿病前期可能是 了解这种加速衰老，因为它可以提供一个了解最初的病理生理的最佳窗口 引发认知功能障碍和阿尔茨海默病的变化。然而，高血糖的作用尚不确定。 在糖尿病前期，可能是因为只使用单个时间点零星地评估血糖峰值 像血红蛋白A1c(HbA1c)和空腹血糖这样的测量得出了血糖紊乱的关键方面 未经审查。这些限制开启了一种可能性，即对血糖异常的更精确测量将产生 对T2 DM病理生理学改变认知功能的机制有更明确的理解 和AD风险，目前尚不清楚。我们将是第一个利用尖端连续葡萄糖 监测(CGM)技术，以调查血糖异常、认知功能、 以及有T2 DM风险的老年人中的关键AD生物标记物。CGM允许精确评估 血糖水平的波动显示出几天来高血糖和低血糖的个性化模式-主要 空腹血糖或糖化血红蛋白中没有反映出的血糖紊乱的成分。因为CGM技术几乎 仅供诊断为T2 DM的人使用，检查T2 DM高危人群是一项创新。我们的 建立了多学科的研究团队，拥有行为医学、内分泌学、老年病学、 神经心理学和神经学，以及多年的合作临床研究经验，是很好的- 在40名有T2 DM风险的老年人中进行研究(A)血糖波动与 情节记忆和执行功能的认知功能障碍，这两个关键领域都显示出两者的减少 在阿尔茨海默病早期和糖尿病前期，以及(B)首次探索血糖与 早期阿尔茨海默病风险生物标志物的波动。这些基于血浆的tau AD生物标记物 磷酸化和淀粉样蛋白负荷具有成本效益，需要微创采血，而且 用于超灵敏免疫分析的血液中脑特异性蛋白质的数量。通过利用精确的、 评估早期血糖波动的可扩展技术，以及早期AD风险的敏感筛查工具，这 创新的建议将在老龄化和AD风险研究方面取得科学和技术进步。 支持我们的假设将引入经济高效、用户友好的CGM技术，作为一种新颖、敏感、 用于早期检测认知功能障碍和AD风险分层的数字生物标记物，最终有助于 老年人在晚年仍能保持认知功能。

PROJECT ABSTRACT Reliable diagnostic digital tools are needed for the early detection of cognitive dysfunction and stratification of early Alzheimer’s Dementia (AD) risk among older adults at risk for Type 2 diabetes (T2DM). T2DM is a well- known accelerator of cognitive decline and AD risk: T2DM is linked to dysfunction in episodic memory and executive functions, and proffers a 2- to 4-fold increased risk for AD. The prediabetes stage may be key to understanding this accelerated aging as it could provide an optimal window into the initial pathophysiological changes that trigger cognitive dysfunction and AD. However, uncertainty surrounds the role of hyperglycemia in the prediabetic stage, perhaps because only assessing peaks in glucose sporadically using single time-point measurements like hemoglobin A1c (HbA1c) and fasting glucose leaves key aspects of dysglycemia unexamined. These limitations open the possibility that more precise measurement of dysglycemia will yield a more definitive understanding of the mechanisms by which T2DM pathophysiology modifies cognitive function and AD risk, which are presently unknown. We will be the first to leverage cutting-edge Continuous Glucose Monitoring (CGM) technology to investigate the precise associations between dysglycemia, cognitive function, and key AD biomarkers in older adults with at risk for T2DM. CGM allows for the precise assessment of fluctuations in glucose levels to show individualized patterns of hyper- and hypoglycemia over days- a major component of dysglycemia not reflected in fasting glucose or HbA1c. Because CGM technology has almost exclusively been used by people with a T2DM diagnosis, examining those at risk for T2DM is innovative. Our established multidisciplinary research team, with expertise in behavioral medicine, endocrinology, geriatrics, neuropsychology, and neurology, and numerous years of collaborative clinical research experience, is well- positioned to examine among 40 older adults at risk for T2DM (a) the association of glycemic fluctuations with cognitive dysfunction in episodic memory and executive functions, key domains that show decrements both early in the AD trajectory, and in prediabetes, and (b) explore, for the first time, the association of glycemic fluctuations with well-established biomarkers of early AD risk. These plasma-based AD biomarkers of tau phosphorylation and amyloid burden are cost-effective, require minimally invasive blood draws, and minute amounts of brain-specific proteins in blood for use with ultrasensitive immunoassays. By leveraging precise, scalable technology to assess early glycemic fluctuations, and sensitive screening tools for early AD risk, this innovative proposal stands to make both scientific and technological advances in aging and AD risk research. Support for our hypotheses would introduce cost-effective, user-friendly CGM technology as a novel, sensitive, digital biomarker for the early detection of cognitive dysfunction and stratification of AD risk, ultimately, helping older adults preserve cognitive function into later life.