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: 10214302
• 负责人: ADAM M BRICKMAN
• 金额: $ 273.01万
• 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/10214302
• 关键词: Affect; African American; 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; Brain; Brain imaging; 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; Structure; Therapeutic Trials; Thick; Time; Universities; Variant; Vascular Diseases; Washington; White Matter Hyperintensity; Whole Blood; base; blood-based biomarker; 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）和分子PET生物标志物Aβ和磷酸化tau的分析