Contribution of child development, biological aging, and beta-amyloid to cognitive function of the Louisville twins at midlife

项目摘要/摘要 这项拟议的研究将澄清中年加速的生物衰老是否预示着更高水平的 临床前AD生物标志物，使用高度可靠的血浆β-淀粉样蛋白(Aβ)标志物进行测量。我们会 研究路易斯维尔双胞胎研究中心(LTS)的750对40岁的双胞胎个体，以检验这一假设 加速衰老有助于Aβ的积累和中年认知功能的变化。我们会找到 并招募这对双胞胎，在加州大学进行面对面的认知功能和身体评估 并从每个双胞胎身上采集50cc的血液，以量化生物年龄、血浆A-β和基因 他们。我们招募双胞胎参加新阶段学习的能力在我们2018年的中年中得到了展示 先导性研究，我们收集认知能力、体格测量和血液来构建生物 老化措施。初步研究结果表明，生物年龄比生理年龄更能预测情景记忆。 全球功能，与先前的研究一致。LTS是唯一一项能够将加速的 衰老、β堆积和中年认知功能与早期认知功能 类似的纵向双胞胎研究样本目前还太年轻。我们将回答两个研究问题： 1)具有加速衰老的遗传和环境倾向的个体是否有更大的Aβ 在中年积累和表现较差的认知？2)早期的发展特征是如何 影响生物衰老、Aβ和中年认知功能？为了解决这些问题，我们将完成 具体目标如下：量化生物衰老的几个标记物，以测试加速衰老 通过收集生物、认知、记忆，预测中年时β的积累和认知功能低下 和来自40岁-(目标1)的双胞胎的功能能力数据；确定Aβ积累是否在 加速衰老对认知功能减退的影响，调整了混淆的遗传和 环境因素(目标2)；评估早期生活特征对加速老化的影响，Aβ 中年的积累和认知功能，对混淆的遗传和环境因素进行调整 (目标3)。这项拟议的研究意义重大，因为它将明确说明加速衰老的因果关系 使用基于血液老化的测量方法预测β的中年积累和认知功能对β的影响 积累，并将调查早期生命发育机制对加速衰老的因果影响， β的积累，以及中年的认知功能。由于这部小说，拟议中的工作具有创新性 一项双生子寿命研究的应用，即加强关于糖尿病影响的因果结论的能力 当随机化是不可能的时候，AD生物标记物在中年加速老化；因为它将建立 血浆的新标准--纵向双胎研究中的β数据收集。与NIA的目标一致，这 该项目将测试加速老化措施作为ADRD风险早期指标的临床效用。

Project Summary/Abstract The proposed study will clarify whether accelerated biological aging at midlife predicts higher levels of preclinical AD biomarkers, as measured using a highly reliable plasma beta-amyloid (Aβ) marker. We will study 750 individual twins age 40-64 from the Louisville Twin Study (LTS) to test the hypothesis that accelerated aging contributes to Aβ accumulation and changes in cognitive functioning in midlife. We will locate and recruit the twins, conduct in-person cognitive functioning and physical assessments at the University of Louisville, and collect 50cc of blood from each twin to quantify biological age, plasma-Aβ, and to genotype them. Our ability to recruit twins to participate for a new phase of study is demonstrated in our 2018 Midlife Pilot Study, in which we collected cognitive ability, physical measurements, and blood to construct a biological aging measure. Preliminary results suggest that biological age is a better predictor of episodic memory than global functioning, consistent with prior research. The LTS is the only twin study capable of linking accelerated aging, Aβ accumulation, and cognitive functioning at midlife to cognitive functioning in early life, as other comparable longitudinal twin study samples are currently too young. We will address two research questions: 1) Do individuals with genetic and environmental predispositions for accelerated aging have greater Aβ accumulation and perform worse cognitively in midlife?; and 2) How do early life developmental characteristics influence biological aging, Aβ, and midlife cognitive functioning? To address these questions, we will complete the following specific aims: Quantify several markers of biological aging to test whether accelerated aging predicts Aβ accumulation and lower cognitive functioning at midlife by collecting biological, cognitive, memory, and functional ability data from LTS twins age 40-64 (Aim 1); Determine whether Aβ accumulation mediates effects of accelerated aging on diminished cognitive functioning, adjusting for confounding genetic and environmental factors (Aim 2); Evaluate effects of early life characteristics on accelerated aging, Aβ accumulation, and cognitive functioning in midlife, adjusting for confounding genetic and environmental factors (Aim 3). The proposed research is significant because it will specify causal effects of accelerated aging in midlife on Aβ accumulation and cognitive functioning, using blood-based aging measures to predict Aβ accumulation, and will investigate causal effects of early life developmental mechanisms on accelerated aging, Aβ accumulation, and cognitive functioning at midlife. The proposed work is innovative because of the novel application of a lifespan twin study, the capability of strengthening causal conclusions about the effects of accelerated aging on AD biomarkers in midlife when randomization is impossible; and because it will establish new standards for plasma-Aβ data collection in longitudinal twin studies. Consistent with NIA’s aims, this project will test the clinical utility of accelerated aging measures as early indicators of ADRD risk.