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

认知障碍和痴呆、血管性脑损伤和心房肌病：对预防阿尔茨海默病相关痴呆的影响

• 批准号: 10814076
• 负责人: Lin Yee Chen
• 金额: $ 439.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814076
• 关键词: Adult; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Atherosclerosis Risk in Communities; Atrial Fibrillation; Biological Markers; Black race; Brain Infarction; Cerebrovascular Trauma; Clinical; Clinical Trials; Cognitive; Communities; Data; Dementia; Disease; Echocardiography; Elderly; Electrocardiogram; Ensure; Epidemiologic Methods; Etiology; Evaluation; Funding; Future; Glial Fibrillary Acidic Protein; Heart; Heart Atrium; Hemorrhage; Hypertension; Image; Imaging technology; Impaired cognition; Incidence; Intervention; Ischemia; Jackson Heart Study; Left; Left Atrial Function; Left Ventricular Mass; Life Style; Light; Measurement; Measures; Molecular; Molecular Target; Monitor; Multi-Ethnic Study of Atherosclerosis; Myopathy; Neurocognitive; Organ; Outcome; Participant; Pathology; Persons; Plasma; Population; Prevention; Prevention strategy; Proteins; Proteomics; Public Health Practice; Reproducibility; Research; Risk Factors; Structure; Time; United States National Institutes of Health; Visit; White Matter Disease; abeta deposition; analytical method; apolipoprotein E-4; cardiovascular disorder risk; clinical practice; cognitive function; cohort; dementia risk; follow-up; heart rhythm; high risk; metabolomics; mild cognitive impairment; modifiable risk; neurofilament; neuroimaging; neuroimaging marker; neuropathology; neurovascular unit; novel; prevent; prognostic; symposium; tau-1; vascular cognitive impairment and dementia; vascular risk factor; wearable device

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.

阿尔茨海默病（AD）和AD相关痴呆（ADRD）预计将影响1.15亿人