Building an unbiased pooled cohort for the study of lifecourse social and vascular determinants of Alzheimer's Disease and Related Disorders

建立一个无偏见的队列研究阿尔茨海默病和相关疾病的生命周期社会和血管决定因素

• 批准号: 10222823
• 负责人: Medellena Maria Glymour
• 金额: $ 81.44万
• 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: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10222823
• 关键词: Address; Adolescent; Adopted; Adult; Affect; African American; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attenuated; Birth; Blood Vessels; Body Weight decreased; Child; Childhood; Cohort Studies; Coronary artery; Data; Data Collection; Data Set; Data Sources; Dementia; Development; Diagnosis; Disease; Elderly; Enrollment; Etiology; Evaluation; Face; Genetic Risk; Geography; Goals; Health; Health and Retirement Study; Heart; Impaired cognition; Individual; Intervention; Lead; Life; Longitudinal Studies; Mendelian randomization; Methodology; Methods; Modeling; National Health and Nutrition Examination Survey; National Longitudinal Survey of Youth; Obesity; Pattern; Phase; Positioning Attribute; Prevention; Process; Public Health; Research; Risk; Risk Factors; Role; Sampling; Socioeconomic Factors; Stroke; Structure; Time; Walking; Woman; base; biological sex; caucasian American; cohort; cost; dementia risk; emerging adult; high risk; improved; men; middle age; multiple data sources; nutrition; prevent; protective factors; racial disparity; research study; social; social factors; socioeconomic disadvantage; tool; vascular factor; vascular risk factor; young adult

Abstract Critical social and vascular risk factors for Alzheimer’s disease and related dementias (ADRD) occur in childhood, early adulthood, or midlife, decades before ADRD is typically diagnosed. Most cohorts dedicated to the study of aging are initiated in mid to late life, and are therefore not ideal for evaluating the effects of early life risk factors. Synthetic cohorts, which pool multiple data sources that in combination span early to late life, provide an unparalleled opportunity to rigorously evaluate lifecourse mechanisms of ADRD. Lifecourse research, especially when based on synthetic cohorts, faces several methodological challenges related to survival, enrollment and attrition that are differential across the pooled studies, and reverse causation from incipient dementia. The long-term goal of our research is to pinpoint how and when we can intervene to prevent or delay the onset of ADRD. Yet, the differential selection forces in a synthetic cohort can make it impossible to identify protective factors, can spuriously make harmful factors appear innocuous, and can provide incorrect guidance on prevention priorities. In this study, we propose to pool eight data sources comprising children, young, middle-aged, and older adults to create a SYNthetic Birth cohort for research on ADRD (SynBAD), correcting for differential survival, enrollment or attrition, and reverse causation, allowing us to rigorously evaluate the effects of lifecourse social and vascular risk factors. SynBAD will include the Bogalusa Heart Study, the Muscatine study, the National Longitudinal Survey of Youth 1979, The National Longitudinal Study of Adolescent to Adult Health, the Coronary Artery Risk in Development in Young Adults, the Health and Retirement Study, the REasons for Geographic And Racial Disparities in Stroke, and the National Health and Nutrition Examination Studies. SynBAD will be large (N=304,171) and exceptionally diverse, facilitating research on the drivers of ADRD among women (56%) and Black individuals (25%). Specifically, we propose to (Aim 1) create a diverse synthetic birth cohort (age 0 to 90) for the study of social and vascular risk factors for ADRD, incorporating corrections for differential survival, enrollment, and attrition; (Aim 2), evaluate and correct for reverse causation -- in which incipient dementia induces changes in risk factors -- by using a reverse Mendelian Randomization approach based on identifying the age-specific effects of a genetic risk score for ADRD on risk factors; (Aim 3), rigorously estimate the causal effects of social and vascular factors on ADRD risk using the synthetic cohort corrected for selection and reverse causation biases; and (Aim 4), quantify reduction in lifetime ADRD cases and ADRD racial disparities that could be achieved with a variety of hypothetical interventions on social or vascular risk factors at different ages. Given the role of biological sex with social and vascular risk factors and dementia risk, we will allow for distinct risk models for men and women. This study will improve the validity of lifecourse research using synthetic cohorts and provide more valid and public health relevant estimates of the effects of social and vascular determinants of ADRD.

抽象的 阿尔茨海默病和相关痴呆 (ADRD) 的关键社会和血管危险因素发生在 大多数群体通常在 ADRD 被诊断之前的童年、成年早期或中年几十年。 衰老研究是在中晚年开始的，因此对于评估早期衰老的影响并不理想。 综合队列，汇集了涵盖早年到晚年的多个数据源， 为严格评估 ADRD 的生命过程机制提供了无与伦比的机会。 研究，尤其是基于合成队列的研究，面临着与以下相关的一些方法学挑战 合并研究中存在差异的生存率、入组率和流失率，以及与 我们研究的长期目标是确定我们如何以及何时进行干预。 然而，合成队列中的差异选择力可以预防或延迟 ADRD 的发生。 无法识别保护因素，可以虚假地使有害因素看起来无害，并且可以 在这项研究中，我们建议汇集八个数据源。 由儿童、青年、中年和老年人组成，创建一个合成出生队列，用于研究 ADRD (SynBAD)，纠正差异生存、入组或自然减员以及反向因果关系，使我们能够 严格评估生命全程社会和血管危险因素的影响。 Bogalusa 心脏研究、马斯卡廷研究、1979 年全国青年纵向调查、国家 青少年到成人健康的纵向研究，年轻人发育中的冠状动脉风险， 健康与退休研究、中风的地理和种族差异的原因以及 国家健康和营养检查研究规模很大（N=304,171）并且非常特殊。 多样化，促进对女性 (56%) 和黑人 (25%) 中 ADRD 驱动因素的研究。 具体来说，我们建议（目标 1）创建一个多样化的合成出生队列（0 至 90 岁）来研究社会 ADRD 的血管危险因素，包括对差异生存、入组和自然减员的校正； （目标 2），评估并纠正反向因果关系——即早期痴呆症会导致风险变化 因素——通过使用基于识别年龄特异性影响的反向孟德尔随机化方法 ADRD 的遗传风险评分对风险因素的影响；（目标 3），严格评估社会和因素的因果影响； 使用校正选择和反向因果偏差的合成队列研究血管因素对 ADRD 风险的影响； （目标 4），可以通过以下方式实现终生 ADRD 病例和 ADRD 种族差异的数量减少： 考虑到不同年龄的社会或血管危险因素的各种假设干预措施的作用。 生物性别与社会和血管危险因素以及痴呆风险，我们将允许不同的风险模型 这项研究将提高使用合成队列的生命历程研究的有效性，并提供 对 ADRD 的社会和血管决定因素的影响进行更有效且与公共卫生相关的估计。