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)的关键社会和血管危险因素发生在 儿童期、成年期早期或中年，通常在ADRD确诊前几十年。大多数人致力于 衰老的研究始于中老年，因此不能很好地评估早期衰老的影响。 生命危险因素。合成队列，它汇集了多个数据源，这些数据源结合在一起，跨越了生命的早期到晚期， 为严格评估ADRD的生命周期机制提供了无与伦比的机会。生命之路 研究，特别是基于合成队列的研究，面临着几个与以下方面有关的方法学挑战 存活率、登记人数和自然减员在合并研究中存在差异，并与 早期痴呆症。我们研究的长期目标是确定我们可以如何以及何时干预 预防或延缓ADRD的发生。然而，合成队列中的差异选择力量可以做到这一点 不可能确定保护因素，可以虚假地使有害因素看起来无害，并且可以 在预防优先事项上提供不正确的指导。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，以创建用于研究的合成出生队列 ADRD(SynBAD)，修正不同的生存、登记或损耗，以及反向因果关系，允许我们 严格评估生命周期、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，国家 青春期与成人健康、青壮年冠状动脉发育风险的纵向研究 健康和退休研究，中风地理和种族差异的原因，以及 国家健康和营养检查研究。SynBAD将非常大(N=304,171) 多样化，促进对妇女(56%)和黑人个人(25%)中的ADRD驱动因素的研究。 具体地说，我们建议(目标1)创建一个多样化的合成出生队列(年龄从0岁到90岁)，用于研究社会 和ADRD的血管危险因素，结合差异生存、登记和消耗的校正； (目标2)，评估和纠正反向因果关系--早期痴呆导致风险变化 因素--通过使用基于确定特定年龄效应的反向孟德尔随机化方法 对ADRD的风险因素进行遗传风险评分；(目标3)，严格估计社会和 血管因素对ADRD风险的影响使用经选择和反向因果偏差校正的合成队列； 和(目标4)，量化可通过以下方式实现的终生ADRD病例和ADRD种族差异的减少 对不同年龄段的社会或血管危险因素进行各种假设性干预。考虑到 生物性行为与社会和血管风险因素以及痴呆症风险，我们将考虑到不同的风险模型 男人和女人。这项研究将提高使用合成队列进行生命周期研究的有效性，并提供 对ADRD的社会和血管决定因素的影响进行更有效和与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.