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.

抽象的。脑脊液（CSF）和Aβ和磷酸-TAU的分子PET生物标志物的分析 结合对全球和区域神经变性的MRI评估，导致了“ A/T/N”的发展 阿尔茨海默氏病（AD）的分类方案，旨在为临床诊断提高精度 目的，治疗试验和监管机构。对于观察性流行病学研究的宽度 由于费用且访问气旋的机会有限，因此无法使用这些类型的生物标志物 在大型研究中获得分子成像和获得CSF的困难所必需的。此外，很明显 生物标志物价值与临床诊断的关系也可能因年龄，性别和种族/种族群体而有所不同，很少 研究包括潜水员队列，代表美国的人口。新的冒险 建立的，基于血液的生物标志物（Aβ40，Aβ42，P-TAU217，神经丝轻链或NFL）结合 Brain MRI提供了一个机会，可以调查“ A/T/N生物标志物配置文件”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型型。 华盛顿高地，Inwood哥伦比亚老化项目（WHICAP）研究是为数不多的人群之一 可以使用新成立的血液基本生物标志物和广为AD的神经成像生物标志物 调查种族/族裔群体以及年龄和性别的基于血液的“ A/T/N生物标志物概况”。淀粉样蛋白 （等离子体Aβ40和Aβ42），tau（等离子体总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）将在纵向的多种族中进行评估 以社区为基础的队列（24％白人非西班牙裔，28％的非裔美国人，48％加勒比西班牙裔）。 该队列的特征很普遍，并存储了DNA，血清和血浆。效果 脑血管疾病“ V”和社会心理因素也将作为潜在的调节剂。 “ A/T/N生物标志物概况”。我们将在非裔美国人，加勒比海西班牙裔中使用公开可用的遗传数据 和非西班牙裔白人参与者，其中包括WHICAP队列以创造特定民族的多基因风险 分数（EPRS）。这将允许识别与基于的内表型相关的变体 “ A/T/N生物标志物概况”并增加了EPRS与AD临床诊断的关联。 我们将维护WHICAP队列的纵向后续行动，仅添加参与者以解释损耗， 为血浆和血清收集全血，确定社会心理和生物医学风险以及保护因素 并在四年期间在参与者中至少获得两次结构MRI测量。总体目标 该项目是：1）调查“ A/T/N生物标志物”中血液基标记物和MRI测量的变异性 特征”适用于多种族队列中的临床诊断； 2）研究基于血液的生物标志物 遗传分析中的内表型，用于早期检测和诊断AD； 3）研究如何 脑血管疾病和社会心理因素调节血液和MRI生物标志物的使用。