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Sex-specific risk factors and trajectories of blood biomarkers for Alzheimer's disease and related dementias

阿尔茨海默病和相关痴呆症的性别特异性危险因素和血液生物标志物轨迹

基本信息

批准号：
10525327
负责人：
ANNE M MURRAY
金额：
$ 415.95万
依托单位：
HENNEPIN HEALTHCARE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525327
关键词：
Address Affect Age Alcohol consumption Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Australia Biological Markers Black American Black Populations Blood Blood specimen Cardiovascular Diseases Characteristics Chronic Clinic Clinical Clinical Trials Cognition Collection Communities Data Dementia Development Diabetes Mellitus Diagnosis Disease Progression Education Elderly Enrollment Ethnic Origin Funding Gender Genetic Genomics Glial Fibrillary Acidic Protein Health Hypertension Impaired cognition Individual Knowledge Life Style Light Longitudinal Studies Longitudinal cohort Measures Mental Depression Methods Minority Modeling Nerve Degeneration Non-Invasive Cancer Detection Outcome Participant Pathology Persons Phenotype Physical activity Plasma Population Positioning Attribute Prevalence Prevention Prognosis Race Reference Values Reporting Research Risk Risk Factors Sampling Sex Differences Smoking Socioeconomic Status Symptoms Time Woman adjudicate aged apolipoprotein E-4 base blood pressure variability blood-based biomarker clinical diagnostics clinical practice cognitive change cognitive function cognitive testing cohort comorbidity cost efficient dementia risk design diagnostic tool executive function genetic risk factor high school insight men neurofilament novel personalized medicine personalized strategies polygenic risk score population based predictive modeling preventive intervention processing speed prognostic tool prospective risk prediction model screening sex social tau Proteins tau-1 tool

项目摘要

PROJECT SUMMARY / ABSTRACT Late-life Alzheimer’s disease and related dementias (ADRD) are devastating multifactorial conditions and the major contributors to loss of independence in older age. There is a critical unmet need to identify which individuals are at the great risk of these conditions, thus permitting accurate prognosis and timely preventative interventions to reduce the burden. Yet, while a number of risk factors have been identified for these conditions, sex differences in these associations have rarely been considered. Furthermore, exciting recent advances in blood amyloid, tau and neurodegeneration (AT(N)) biomarkers for ADRD means that they could soon be used as powerful clinical diagnostic and prognostic tools in a personalized medicine approach. However, a number of critical knowledge gaps remain. Importantly, 1) these biomarkers have not been sufficiently examined in longitudinal studies of older community- based populations without diagnosed dementia; 2) it is unclear how participant characteristics such as comorbidities affect the clinical interpretation of these biomarkers; and 3) how their interpretation may differ between men and women. Together, these large knowledge gaps highlight a crucial need to develop the first sex-specific risk score for ADRD that incorporates blood AT(N) biomarkers and ADRD risk factors. Our overarching hypothesis is that AT(N) plasma biomarkers will be predictive of ADRD in initially healthy community-dwelling older individuals, beyond known risk factors (including age, education, living alone, diabetes, hypertension, smoking, alcohol consumption, physical activity), and that these associations will vary by sex. This project provides an unprecedented opportunity to address this important question within the context of a rigorous, large-scale study of initially healthy individuals aged 65-98 years from the US and Australia (12,716 whites, 412 blacks, 339 other minorities) with comprehensive annual in-person cognitive assessments, adjudicated clinical outcomes, detailed data on socio-economic status, lifestyle and health factors collected over a median 9+ years, and existing genetic data (APOE4, dementia polygenic risk scores). Leveraging unique blood samples available at two time-points (n=13,435 at baseline, and ~8000 at 7 to 10 years), AT(N) biomarkers will be measured longitudinally. This proposal is a unique, highly cost-efficient opportunity to address gaps in our ability to accurately determine who is at the greatest risk of ADRD, individually for women and men. We will address critical gaps in identifying which factors influence blood biomarker levels and must be considered when establishing their clinical reference ranges. The sex-specific risk score resulting from this project will provide a powerful new tool for practitioners to predict risk of cognitive decline and ADRD that considers common comorbidities, social, lifestyle, and genomic risk factors, together with the unique predictive strength of the plasma AT(N) biomarkers.

项目总结/摘要老年阿尔茨海默病和相关痴呆（ADRD）是一种破坏性的多因素疾病，老年人丧失独立性的主要原因。有一个关键的未得到满足的需要，个人有很大的风险，这些条件，从而允许准确的预后和及时的预防采取措施减轻负担。然而，虽然已经确定了这些疾病的一些风险因素，这些关联中的性别差异很少被考虑。此外，令人兴奋的最新进展， ADRD的血液淀粉样蛋白、tau蛋白和神经变性（AT（N））生物标志物意味着它们很快就可以用于作为个性化医疗方法中强大的临床诊断和预后工具。但若干关键的知识差距依然存在。重要的是，1）这些生物标志物在临床上没有得到充分的检查，对未诊断为痴呆症的老年社区人群的纵向研究; 2）尚不清楚如何参与者的特征，如合并症，影响这些生物标志物的临床解释;以及3）如何对这些问题的解释在男女之间可能有所不同。总之，这些巨大的知识差距突出了一个关键的需要开发第一个ADRD的性别特异性风险评分，其中包括血液AT（N）生物标志物和ADRD 危险因素我们的总体假设是，AT（N）血浆生物标志物将预测ADRD在最初健康的人，社区居住的老年人，除了已知的风险因素（包括年龄，教育，独居，糖尿病，高血压、吸烟、饮酒、体育活动），这些关联因性别而异。该项目提供了一个前所未有的机会，以解决这一重要问题的背景下，对美国和澳大利亚年龄在65-98岁之间的最初健康个体进行了严格的大规模研究（12，716 白人，412名黑人，339名其他少数民族）进行全面的年度面对面认知评估，判定的临床结局，收集的社会经济状况、生活方式和健康因素的详细数据， a中位数9岁以上，现有遗传数据（APOE 4，痴呆多基因风险评分）。利用独特的血液两个时间点的样本（基线时n= 13，435，7 - 10年时约8000），AT（N）生物标志物将纵向测量。这一提案是一个独特的、具有高度成本效益的机会，可以弥补我们在能够准确地确定谁是ADRD的最大风险，分别为女性和男性。我们将解决在确定哪些因素影响血液生物标志物水平方面的关键差距，建立其临床参考范围。该项目产生的性别特异性风险评分将提供一个从业者预测认知能力下降和ADRD风险的强大新工具，合并症，社会，生活方式和基因组风险因素，以及独特的预测能力，血浆AT（N）生物标志物。