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

项目摘要/摘要 老年阿尔茨海默病和相关痴呆(ADRD)是破坏性的多因素疾病， 导致老年人丧失独立性的主要因素。有一个关键的未得到满足的需求，即确定哪些 个人面临这些情况的巨大风险，因此可以进行准确的预测和及时的预防 采取干预措施减轻负担。然而，尽管已经确定了这些情况的一些风险因素， 这些关联中的性别差异很少被考虑。此外，令人振奋的最新进展 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使用 作为个性化医疗方法中强大的临床诊断和预后工具。然而，一些人 关键的知识差距依然存在。重要的是，1)这些生物标志物还没有得到充分的研究 对未诊断为痴呆症的社区老年人群的纵向研究；2)尚不清楚是如何进行的 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 他们的解释可能在男性和女性之间有所不同。总之，这些巨大的知识差距突显了一个至关重要的 需要开发第一个性别特定的ADRD风险评分，其中包括血液AT(N)生物标记物和ADRD 风险因素。 我们的主要假设是AT(N)血浆生物标志物将预测最初健康的ADRD 社区居住的老年人，除了已知的危险因素(包括年龄、教育、独居、糖尿病、 高血压、吸烟、饮酒、体力活动)，而且这些联系因性别而异。 这个项目提供了一个前所未有的机会，在一个 对美国和澳大利亚(12,716名)年龄在65-98岁之间的初步健康的人进行了严格的大规模研究 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， 对临床结果作出判断，收集关于社会经济状况、生活方式和健康因素的详细数据 中位数为9岁以上，现有遗传数据(APOE4，痴呆症多基因风险评分)。利用独特的血液 在两个时间点(基线时n=13,435，7至10年后~8000)可获得样本，AT(N)生物标志物将 被纵向测量。这项建议是一个独特且经济高效的机会，可以弥补我们在 能够准确地确定谁是ADRD风险最大的人，无论是女性还是男性。我们会 解决在确定哪些因素影响血液生物标记物水平方面的关键差距，以及在以下情况下必须考虑 建立他们的临床参考范围。此项目产生的特定性别的风险分数将提供 为从业者提供了强大的新工具来预测认知能力下降和ADRD的风险 合并症、社会、生活方式和基因组风险因素，以及 血浆AT(N)生物标志物。

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.