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，阿尔茨海默病及相关痴呆症(ADRD)成为人们日益关注的健康问题。虽然已经开发和测试了许多治疗ADRD的有希望的方法，但它们在很大程度上未能预防疾病的发病或减缓老年人的疾病进展。然而，研究发现，ADRD病理的细微迹象在疾病发作前几十年就可以检测到。为了开发能够在大脑发生顽固性恶化之前减缓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，并开发能够将中年衰老的微妙个体差异迹象与晚年ADRD联系起来的生物标记物。在拟议的研究的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的方法调查潜在的替代生物标记物，达尼丁研究是目前处于中年的人口代表出生队列。具体地说，候选人将调查在老年人中广泛使用的ADRD风险测量方法，包括白质高信号和脑年龄，以衡量中年认知和生物衰老加速的能力。然后，候选人将开发一种跨越19个生物标记物的20年生物老化的纵向测量方法，以调查生物衰老速度加快对中年大脑结构完整性的个体差异的影响。然后，候选人将利用童年时期接触神经毒素铅，这是ADRD的已知风险因素，进一步检查这些候选替代生物标记物的效用，以捕捉中年大脑老化的风险相关特征。在拟议研究的K00阶段，候选人将利用在中年创造生物衰老速度时开发的统计技术，来衡量健康老龄化和老年人ADRD中大脑生物标记物的相关下降。拟议的研究将产生测量中年和老年人加速生物衰老的技术，以及通过应用这些措施对ADRD的洞察。重要的是，拟议的项目将提供对中年和晚年加速老龄化之间的联系的更深层次的理解，这将有助于加大针对生命早期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.