Cognitive Impairment and Dementia, Vascular Brain Injury, and Atrial Myopathy: Implications for Prevention of Alzheimer's Disease-Related Dementias

阿尔茨海默病（AD）和AD相关痴呆症（ADRD）预计将影响1.15亿人 到2050年全球血管对认知障碍和痴呆的贡献（VCID）-一种主要类型的 ADRD是NIH的一个主要研究重点，它呼吁需要发现新的非侵入性， 非CNS器官相关的（例如，心脏）标记物，以检测VCID（ADRD峰会）的存在和进展 2022年）。在世界大部分地区，最高龄者（>85岁）是人口中增长最快的部分， 痴呆症的发病率最高然而，对高龄老人AD/ADRD的危险因素了解甚少 与中老年（65-74岁）和中老年（75-84岁）不同。例如，在最古老的- 高血压是保护性的，大约一半的痴呆病例与非AD病理学有关， 微出血和小血管缺血性疾病。心房肌病（定义为左心房[LA]功能改变或 结构）是VCID的一个未被充分认识但重要的贡献者，并且与较低的认知能力相关。 功能，更大的血管性脑损伤，以及痴呆症的发生。心房肌病也与更大的 整体皮质β-淀粉样蛋白（AD病理学）。然而，心房肌病变与 老年痴呆症的风险是未知的。此外，先前的研究已经评估了心房肌病作为一种 静态实体和心房肌病进展的病因学和预后相关性尚不清楚。这些 是针对这一潜在可改变的风险因素进行AD/ADRD预防的关键障碍。因此 本项目的首要目标是确定心房肌病变对事件的预后重要性。 高龄老年痴呆症;与高龄老年心房肌病进展或轨迹相关 和中老年至偶发性痴呆以及AD/ADRD的神经影像学和血浆生物标志物的变化;以及 确定不良心房肌病变的临床/生活方式风险因素以及蛋白质组学和代谢组学特征 轨迹我们将利用社区中广泛描述的动脉粥样硬化风险（ARIC） 队列（包括随访时间最长的黑人成年人队列），现有MCI/痴呆确定， 神经影像学数据，并将进行LA功能的系列测量，测量循环AD/ADRD 生物标志物，并进行动态心律监测，以严格检测房颤（AF）， 我们可以解释AF对协会的贡献。为了确保严谨性和可重复性，我们将复制 两个独立的社区队列研究结果：动脉粥样硬化和杰克逊的多种族研究 心脏研究。该项目将产生重大影响。我们的研究结果将（a）将VCID扩展到包括心房 肌病作为对神经血管单位的损伤，从而确定了AD/ADRD治疗的新途径，或 预防;（B）阐明心房肌病的神经认知影响的病理学基础，从而促进 研究发现新的AD/ADRD预防策略;（c）确定特定的生活方式或分子靶点， 心房肌病进展，从而为未来旨在预防AD/ADRD的临床试验提供信息。

Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD) are projected to affect 115 million people worldwide by 2050. Vascular contributions to cognitive impairment and dementia (VCID)—a primary type of ADRD—is a major research focus for the NIH, which has called for the need to discover novel non-invasive, non-CNS organ-related (e.g., heart) markers to detect presence and progression of VCID (ADRD summit 2022). The oldest-old (>85 years) are the fastest growing segment of the population in most of the world and have the highest rates of dementia. Yet, the risk factors for AD/ADRD in the oldest-old are poorly understood and are different from the young-old (65-74 years) and middle-old (75-84 years). For example, in the oldest- old, hypertension is protective and about half of all dementia cases is related to non-AD pathologies such as microbleeds and small vessel ischemic disease. Atrial myopathy (defined by altered left atrial [LA] function or structure) is an underrecognized but important contributor to VCID, and is associated with lower cognitive function, greater vascular brain injury, and incident dementia. Atrial myopathy is also associated with greater global cortical β-amyloid (AD pathology). However, the extent to which atrial myopathy is associated with dementia risk in the oldest-old is unknown. Furthermore, prior research has evaluated atrial myopathy as a static entity and the etiology and prognostic relevance of atrial myopathy progression are not known. These are crucial barriers to targeting this potentially modifiable risk factor for AD/ADRD prevention. Thus, the overarching objectives of this project are to determine the prognostic importance of atrial myopathy for incident dementia in the oldest-old; relate atrial myopathy progression or trajectories of atrial myopathy in the young-old and middle-old to incident dementia and change in neuroimaging and plasma biomarkers of AD/ADRD; and define the clinical/lifestyle risk factors and proteomic and metabolomic signatures of adverse atrial myopathy trajectories. We will leverage the extensively well-characterized Atherosclerosis Risk in Communities (ARIC) cohort (including the longest followed cohort of Black adults) with existing MCI/dementia ascertainment and neuroimaging data, and will perform serial measurement of LA function, measure circulating AD/ADRD biomarkers, and conduct ambulatory heart rhythm monitoring to rigorously detect atrial fibrillation (AF) so that we can account for the contribution of AF to associations. To ensure rigor and reproducibility, we will replicate findings in 2 independent community-based cohorts: Multiethnic Study of Atherosclerosis and the Jackson Heart Study. This project will have significant impact. Our findings will (a) broaden VCID to encompass atrial myopathy as an insult to the neurovascular unit, thus identifying a new avenue for AD/ADRD treatment or prevention; (b) clarify the pathology underlying the neurocognitive impact of atrial myopathy, hence facilitating research to discover novel AD/ADRD prevention strategies; (c) identify specific lifestyle or molecular targets for atrial myopathy progression, thus informing future clinical trials aimed at preventing AD/ADRD.