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

儿童发育、生物衰老和β-淀粉样蛋白对路易斯维尔双胞胎中年认知功能的贡献

• 批准号: 10409686
• 负责人: Christopher Ryan Beam
• 金额: $ 99.64万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409686
• 关键词: Activities of Daily Living; Address; Adolescence; Adult; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Autopsy; Biological; Biological Aging; Biological Markers; Biological Process; Blood; Characteristics; Child Development; Childhood; Chronology; Clinical; Cognition; Cognitive; Consent; DNA Methylation; Data; Data Collection; Data Set; Development; Educational Status; Environmental Risk Factor; Episodic memory; Genetic; Genetic study; Genotype; Human; Impaired cognition; Individual; Intelligence; Life; Light; Link; Literature; Longevity; Longitudinal Studies; Measurement; Measures; Mediating; Memory; Memory Loss; Methodology; Nature; Neurobehavioral Manifestations; Outcome; Participant; Pathway interactions; Persons; Phase; Physical assessment; Pilot Projects; Plasma; Predisposition; Randomized; Research; Resources; Risk; Sampling; Sampling Studies; Serum; Specific qualifier value; Testing; Twin Multiple Birth; Twin Studies; Work; abeta accumulation; base; cognitive ability; cognitive function; dementia risk; design; functional decline; infancy; innovation; methylation biomarker; middle age; peer; pre-clinical; recruit; resilience; socioeconomics

Project Summary/Abstract The proposed study will test whether accelerated biological aging at midlife predicts higher levels of preclinical AD biomarkers, as measured with a highly reliable plasma beta-amyloid (Aβ) marker, and whether the Aβ accumulation contributes to cognitive decline in midlife. The causal basis of the associations will be established by studying 750 individual twins age 40-64 from the Louisville Twin Study (LTS), who were studied extensively in childhood. We will relocate and recruit the twins, conduct in person cognitive functioning and physical assessments, collect 50cc of blood to quantify biological age, plasma-Aβ, and genotype. Our ability to recruit twins to the new phase of study is demonstrated by our 2018 Midlife Pilot Study, in which we collected cognitive ability, physical measurements, and blood to construct a biological aging measure for 40 participants, with a consent rate of 100%. Preliminary results suggest that accelerated 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 biological aging, Aβ accumulation, and cognitive functioning at midlife to cognitive functioning in childhood, as other comparable longitudinal twin study samples are currently too young. Our study will address two research questions that can only be answered by longitudinal twin studies with intensive childhood measurements: 1) Do people with genetic and environmental predispositions for accelerated biological aging have greater Aβ accumulation and perform worse cognitively in midlife?; and 2) Do early life developmental characteristics cause accelerated biological aging, Aβ, and midlife cognitive functioning? We will complete the following specific aims: Quantify several markers of biological aging to test whether accelerated biological 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 biological aging on declining cognitive functioning, adjusting for confounding genetic and environmental factors (Aim 2); Evaluate effects of early life characteristics on accelerated biological aging, Aβ accumulation, and cognitive functioning in midlife, adjusting for confounding genetic and environmental factors (Aim 3). The significance of the proposed research is specifying causal effects of biological aging in midlife on Aβ accumulation and cognitive functioning, using blood-based aging measures to predict Aβ accumulation, and specifying causal effects of early life developmental mechanisms on accelerated biological aging, Aβ accumulation, and cognitive functioning at midlife. The innovation of the proposed work is the application of a longitudinal twin design, affording us the capability to establish causal effects of biological aging on preclinical AD outcomes in humans for whom experimental randomization is not possible; and establishing new standards for plasma-Aβ data collection in longitudinal twin studies. Consistent with NIA's aims, this project will test the clinical utility of biological aging measures as early indicators of ADRD risk.

项目摘要/摘要 这项拟议的研究将测试中年加速的生物衰老是否预示着更高的临床前水平 AD生物标志物，如用高度可靠的血浆β-淀粉样蛋白(Aβ)标志物测量，以及Aβ是否 积累会导致中年认知能力下降。将建立协会的因果关系基础 通过研究路易斯维尔双胞胎研究所(LTS)的750对40岁的双胞胎-，他们得到了广泛的研究 在童年时。我们将重新安置和招募这对双胞胎，亲自进行认知功能和身体检查 评估，收集50cc的血液以量化生物学年龄、血浆A-β和基因。我们招募人才的能力 我们2018年的中年试点研究证明了双胞胎进入新的研究阶段，在该研究中，我们收集了认知 能力、身体测量和血液，为40名参与者构建生物老化测量，并具有 同意率为100%。初步结果表明，加速的生物年龄是发作的更好的预测因子 记忆多于整体功能，这与之前的研究一致。LTS是唯一一项能够将 生物衰老、β积累和中年认知功能到童年认知功能，如 其他类似的纵向双胞胎研究样本目前还太年轻。我们的研究将涉及两项研究 只有通过对双胞胎进行深入的童年测量才能回答的问题：1)做 具有加速生物衰老的遗传和环境易感性的人有更大的Aβ 在中年积累和表现较差的认知？2)早期的发展特征导致 生物衰老加速、Aβ和中年认知功能？我们将完成以下具体目标： 量化生物老化的几个标记物以检验加速生物老化是否能预测β 通过收集生物、认知、记忆和功能，在中年积累和降低认知功能 来自40岁-的双胞胎的能力数据(目标1)；确定β积累是否介导了 加速生物衰老对认知功能下降的影响，对混淆的基因和 环境因素(目标2)；评估早期生命特征对加速生物衰老的影响，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)。这项拟议的研究的意义在于明确了中年生物衰老的因果关系 Aβ堆积和认知功能，使用基于血液的老化测量来预测Aβ堆积，以及 说明早期生命发育机制对加速生物衰老的因果影响，Aβ 积累和中年的认知功能。拟议工作的创新之处在于应用了 纵向双胞胎设计，使我们能够确定生物老化对临床前的因果影响 不可能进行实验性随机化的人类的AD结果；并建立新的标准 用于血浆-纵向双胞胎研究中的β数据收集。与NIA的目标一致，该项目将测试 生物老化措施作为ADRD风险的早期指标的临床实用性。