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

摘要 阿尔茨海默病和相关痴呆（ADRD）的关键社会和血管风险因素发生在 儿童期、成年早期或中年，通常在ADRD被诊断之前几十年。大多数队列致力于 对衰老的研究是在中年到晚年开始的，因此对于评估早期衰老的影响并不理想。 生命危险因素。合成队列，汇集了多个数据源，这些数据源组合在一起，跨越了生命的早期到晚期， 为严格评估ADRD的生命过程机制提供了无与伦比的机会。生命历程 研究，特别是基于合成群组的研究，面临着与以下方面有关的若干方法学挑战： 汇总研究中的生存率、入组率和损耗率存在差异， 早期痴呆我们研究的长期目标是确定我们如何以及何时可以进行干预， 预防或延缓ADRD的发作。然而，在一个合成的队列中， 不可能识别保护因素，可以虚假地使有害因素看起来无害，并且可以 在预防优先事项方面提供不正确的指导。在这项研究中，我们建议汇集八个数据源， 包括儿童、年轻人、中年人和老年人，以创建一个合成出生队列，用于研究 ADRD（SynBAD），校正差异生存率，招募或流失，以及反向因果关系，使我们能够 严格评估生命过程中的社会和血管危险因素的影响。SynBAD将包括 博加卢萨心脏研究、马斯卡廷研究、1979年全国青年纵向调查、全国 青少年至成年人健康的纵向研究，年轻人发展中的冠状动脉风险， 健康和退休研究，中风的地理和种族差异的原因， 国家健康和营养检查研究。SynBAD将很大（N= 304，171）， 多样化，促进了对妇女（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），用于研究社会 和ADRD的血管危险因素，包括对差异生存率、入组和损耗的校正; (Aim 2），评估和纠正反向因果关系-其中早期痴呆症引起风险的变化 因素-通过使用基于识别年龄特异性效应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），严格估计社会和 血管因素对ADRD风险的影响，使用校正了选择和反向因果关系偏倚的合成队列; 和（目标4），量化减少终身ADRD病例和ADRD种族差异， 在不同年龄段对社会或血管危险因素进行各种假设性干预。鉴于 生物性别与社会和血管风险因素和痴呆风险，我们将允许不同的风险模型， 男人和女人本研究将提高使用合成队列的生命过程研究的有效性，并提供 ADRD的社会和血管决定因素的影响的更有效和公共卫生相关的估计。

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.