Epidemiological and Genetic Investigations of Blood-Based Biomarkers for Alzheimer's Disease in the Multiethnic, Washington Heights, Inwood, Columbia Aging Project (WHICAP)

多民族、华盛顿高地、因伍德、哥伦比亚老龄化项目 (WHICAP) 中阿尔茨海默病血液生物标志物的流行病学和遗传学调查

• 批准号: 10407545
• 负责人: ADAM M BRICKMAN
• 金额: $ 266.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407545
• 关键词: Affect; African American; African American population; African Caribbean; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Autopsy; Biological; Biological Markers; Blood; Caribbean Hispanic; Cerebrospinal Fluid; Cerebrovascular Disorders; Classification; Classification Scheme; Clinical; Cognition; Cognitive; Communities; Community Networks; Cross-Sectional Studies; Cyclotrons; DNA; Data; Data Set; Dementia; Development; Diagnosis; Disease; Early Diagnosis; Education; Elderly; Environment; Epidemiology; Ethnic Origin; Ethnic group; Genetic; Genetic Predisposition to Disease; Genetic Research; Genotype; Goals; Image; Impaired cognition; Individual; Infarction; Investigation; Life Cycle Stages; Light; Magnetic Resonance Imaging; Measures; Mexican Americans; Mind; Molecular; Neighborhoods; Nerve Degeneration; Not Hispanic or Latino; Observational Study; Occupations; Outcome; Participant; Phenotype; Plasma; Population; Positron-Emission Tomography; Psychosocial Factor; Quantitative Trait Loci; Race; Risk Factors; SNP array; SNP genotyping; Sampling; Socioeconomic Status; Therapeutic Trials; Thick; Time; Universities; Variant; Vascular Diseases; Washington; White Matter Hyperintensity; Whole Blood; base; blood-based biomarker; brain magnetic resonance imaging; brain volume; cerebral atrophy; clinical diagnosis; cohort; endophenotype; epidemiology study; exome; follow-up; forest; genetic analysis; genome sequencing; genome-wide; health care availability; health disparity; imaging biomarker; improved; indexing; longitudinal analysis; magnetic resonance imaging biomarker; metabolic abnormality assessment; mild cognitive impairment; molecular imaging; multi-ethnic; neurofilament; neuroimaging marker; phenotypic data; polygenic risk score; prospective; protective factors; psychosocial; racial and ethnic; sex; social; social health determinants; tau Proteins; tau-1

ABSTRACT. The analysis of cerebrospinal fluid (CSF) and molecular PET biomarkers of Aβ and phospho-tau combined with MRI assessment of global and regional neurodegeneration led to the development of the “A/T/N” classification scheme for Alzheimer's disease (AD) that was intended to add precision to the diagnosis for clinical purposes, therapeutic trials and regulatory agencies. For observational epidemiological research the widespread use of these types of biomarkers is not possible because of the expense and limited access to cyclotrons necessary for molecular imaging and the difficulty in obtaining CSF in large studies. Further, it is clear that the relationship of biomarker values to clinical diagnoses can also differ by age, sex and race/ethnic group, and few studies have included diverse cohorts, representative of the population in the US. The advent of newly- established, blood-based biomarkers (Aβ40, Aβ42, p-tau217, neurofilament light chain or NFL) combined with brain MRI provides an opportunity to investigate the application of “A/T/N biomarker profile” in community-based, observational study, and create endophenotypes that can be used to identify genetic susceptibility. The Washington Heights, Inwood Columbia Aging Project (WHICAP) study is one of the few cohorts where the newly established blood-based biomarkers and well-established neuroimaging biomarkers for AD can be used to investigate a blood-based “A/T/N biomarker profile” across race/ethnic groups and by age and sex. Amyloid (plasma Aβ40 and Aβ42), Tau (plasma total tau and p-tau217), and Neurodegeneration (plasma neurofilament light [NfL], and MRI (brain volumes and cortical thickness) will be assessed in a longitudinal, multi-ethnic community-based elderly cohort (24% white non-Hispanic, 28% African American, 48% Caribbean Hispanic). The cohort has been genetically characterized, and has stored DNA, sera, and plasma. The effects of cerebrovascular disease “V” and psychosocial factors will also be investigated as potential modulators of the “A/T/N biomarker profile”. We will use publicly available genetic data in African American, Caribbean Hispanic and non-Hispanic white participants that included the WHICAP cohort to create ethnic-specific polygenic risk scores (ePRS). This will allow the identification of variants associated with the endophenotypes underlying the “A/T/N biomarker profile” and augment the ePRS association with the clinical diagnoses of AD. We will maintain longitudinal follow-up of the WHICAP cohort, adding participants only to account for attrition, collecting whole blood for plasma and sera, ascertaining psychosocial and biomedical risk and protective factors and obtaining structural MRI measures at least twice in participants over a four-year period. The overall goals of this project are to: 1) investigate variability in blood-based biomarkers and MRI measures in the “A/T/N biomarker profile” as it applies to clinical diagnoses in a multi-ethnic cohort; 2) investigate blood-based biomarkers as endophenotypes in genetic analyses for earlier detection and diagnosis of AD; 3) investigate how cerebrovascular disease and psychosocial factors modulate the use of blood-based and MRI biomarkers.

摘要：脑脊液 (CSF) 和 Aβ 和磷酸 tau 分子 PET 生物标志物的分析 结合对整体和区域神经退行性变的 MRI 评估，开发了“A/T/N” 阿尔茨海默病 (AD) 的分类方案旨在提高临床诊断的精确度 目的、治疗试验和监管机构广泛进行观察性流行病学研究。 由于费用昂贵且回旋加速器的使用机会有限，不可能使用这些类型的生物标记物 分子成像所必需的以及在大型研究中获得脑脊液的难度，此外，很明显， 生物标志物值与临床诊断的关系也可能因年龄、性别和种族/族裔群体的不同而不同，而且很少有 研究涵盖了代表美国人口的不同群体。 已建立的血液生物标志物（Aβ40、Aβ42、p-tau217、神经丝轻链或 NFL）与 脑 MRI 提供了一个机会来研究“A/T/N 生物标志物谱”在基于社区的、 观察性研究，并创建可用于识别遗传易感性的内表型。 华盛顿高地、因伍德哥伦比亚老龄化项目 (WHICAP) 研究是少数几个研究 可以使用新建立的血液生物标志物和成熟的 AD 神经影像生物标志物 调查跨种族/族裔群体以及年龄和性别的基于血液的“A/T/N 生物标志物谱”。 （血浆 Aβ40 和 Aβ42）、Tau（血浆总 tau 和 p-tau217）和神经变性（血浆神经丝 光 [NfL] 和 MRI（脑体积和皮质厚度）将以纵向、多种族的方式进行评估 以社区为基础的老年人群体（24% 为非西班牙裔白人，28% 为非洲裔美国人，48% 为加勒比西班牙裔）。 该群体已进行了基因鉴定，并储存了 DNA、血清和血浆。 脑血管疾病“V”和心理社会因素也将作为潜在的调节因素进行研究 “A/T/N 生物标志物概况”。我们将使用非裔美国人、加勒比西班牙裔的公开遗传数据。 和非西班牙裔白人参与者，其中包括 WHICAP 队列，以创建种族特定的多基因风险 分数（ePRS），这将允许识别与潜在的内表型相关的变异。 “A/T/N 生物标志物概况”并增强 ePRS 与 AD 临床诊断的关联。 我们将保持对 WHICAP 队列的纵向随访，仅增加参与者以考虑人员流失， 采集全血作为血浆和血清，确定社会心理和生物医学风险和保护因素 四年内至少两次对参与者进行结构性 MRI 测量 总体目标。 该项目旨在：1) 研究“A/T/N 生物标志物”中基于血液的生物标志物和 MRI 测量的变异性 2) 研究血液生物标志物 用于早期检测和诊断 AD 的基因分析中的内表型 3) 研究如何进行； 脑血管疾病和心理社会因素调节基于血液和生物标志物 MRI 的使用。