Training in lifespan behavioral, social, and neuroscience research connecting early-life cognitive decline to late-life ADRD

随着全球人口老龄化，阿尔茨海默病和相关痴呆症（ADRD）代表了日益增长的健康问题。虽然已经开发和测试了许多有希望的ADRD治疗方法，但它们在很大程度上未能预防老年人的疾病发作或减缓疾病进展。然而，研究发现，ADRD病理学的微妙迹象在疾病发作前几十年就可检测到。为了在大脑发生顽固性恶化之前开发可以减缓ADRD进展的治疗方法，我们需要更好地了解认知，生物和大脑老化的寿命轨迹，并开发生物标志物，可以将中年衰老中个体差异的细微迹象与晚年的ADRD联系起来。 在拟议研究的F99阶段，候选人将描述中年大脑老化的特征，并在达尼丁研究中使用多方面方法研究潜在的替代生物标志物，达尼丁研究是一个具有代表性的人口出生队列，目前处于中年。具体而言，候选人将调查广泛使用的老年人ADRD风险指标的能力，包括白色高信号和脑年龄，以测量中年加速的认知和生物老化。然后，候选人将从20年的生物老化中开发一个纵向测量，跨越19个生物标志物，以研究生物老化加速对中年大脑结构完整性个体差异的影响。然后，候选人将使用儿童期暴露于神经毒素铅（ADRD的一个已知风险因素），以进一步检查这些候选替代生物标志物的效用，以捕获中年大脑老化的风险相关特征。 在拟议研究的K00阶段，候选人将利用在创建中年生物衰老速度时开发的统计技术，来测量健康衰老和老年人ADRD中大脑生物标志物的相关下降。 拟议的研究将产生技术来测量中年和老年人的加速生物衰老，以及通过应用这些措施对ADRD的见解。重要的是，拟议的项目将提供更深入的了解中年和晚年加速老化之间的联系，这将有助于在生命早期进行针对ADRD干预的努力。

Alzheimer’s disease and related dementias (ADRD) represent a growing health concern as the global population ages. While many promising treatments for ADRD have been developed and tested, they have largely failed to prevent disease onset or slow disease progression in older adults. However, research has found that subtle signs of ADRD pathology are detectable decades before disease onset. To develop treatments that can slow the progression of ADRD before intractable deterioration of the brain has taken place, we will need to better understand the lifespan trajectory of cognitive, biological and brain aging and develop biomarkers that can connect subtle signs of individual differences in midlife aging to ADRD in late life. In the F99 phase of the proposed research, the candidate will characterize signatures of midlife brain aging and investigate potential surrogate biomarkers using a multi-faceted approach in the Dunedin Study, a population representative birth cohort now in midlife. Specifically, the candidate will investigate the ability of widely used measures of risk for ADRD in older adults, including white matter hyperintensities and brain age, to measure accelerated cognitive and biological aging in midlife. The candidate will then develop a longitudinal measure from 20 years of biological aging across 19 biomarkers to investigate the consequences of accelerated pace of biological aging on individual differences in the structural integrity of the brain in midlife. Then the candidate will use childhood exposure to the neurotoxin lead, a known risk factor for ADRD, to further examine the utility of these candidate surrogate biomarkers to capture risk-related features of midlife brain aging. In the K00 phase of the proposed research, the candidate will utilize statistical techniques, developed when creating the pace of biological aging in midlife, to measure correlated decline in brain biomarkers in healthy aging and ADRD in older adults. The proposed research will yield techniques to measure accelerated biological aging in midlife and in older adults, as well as insights into ADRD through application of these measures. Critically, the proposed project will provide a deeper understanding of connections between midlife and late life accelerated aging that will contribute to growing efforts to target ADRD intervention earlier in life.