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（ADRD）代表了一个日益严重的健康问题。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病理的细微迹象在发病前几十年就可以检测到。为了在大脑发生难治性恶化之前开发出能够减缓ADRD进展的治疗方法，我们需要更好地了解认知、生物和大脑衰老的生命轨迹，并开发出能够将中年衰老个体差异的细微迹象与晚年ADRD联系起来的生物标志物。在F99阶段，候选人将在达尼丁研究（Dunedin Study）中描述中年大脑衰老的特征，并使用多方面的方法研究潜在的替代生物标志物。达尼丁研究是一项具有代表性的中年出生队列研究。具体而言，该候选人将研究广泛使用的老年人ADRD风险测量方法的能力，包括白质高强度和脑年龄，以测量中年加速的认知和生物衰老。然后，候选人将从20年的19个生物标志物的生物衰老中进行纵向测量，以研究生物衰老速度加快对中年大脑结构完整性个体差异的影响。然后，候选人将利用儿童时期接触神经毒素铅（一种已知的ADRD风险因素）来进一步检查这些候选替代生物标志物的效用，以捕获中年大脑衰老的风险相关特征。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的见解。至关重要的是，拟议的项目将提供对中年和晚年加速衰老之间联系的更深入理解，这将有助于在生命早期针对ADRD进行干预。

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.