Identifying potentially modifiable exposures to improve telomere health and disease outcomes

项目摘要/摘要 端粒磨损是衰老的关键标志。端粒是重复的序列 TTAGGG位于染色体末端，随着年龄的增长而缩短，细胞进入 当端粒达到极短的长度时，就会出现衰老。观测性和 遗传学研究表明，血液中较短的端粒长度(TL)与 阿尔茨海默病(AD)的风险增加。然而，这项研究的样本量是 规模相对较小，2016年的荟萃分析仅包括860名AD患者和2022名 来自13项研究的对照。越来越多的证据表明大脑会发生变化 在诊断出阿尔茨海默病或其相关痴呆(AD/ADRD)前数年。 虽然TL和AD/ADRD之间的关系可能是因果关系，但关联 目标语与认知功能或下降之间的不一致和检验目标语的研究 与大脑成像特征的联系在很大程度上是缺失的。为了填补这些空白，我们 建议使用已有的脑磁共振成像(MRI)数据 100,000名参与者在我们母公司的资助下建立英国生物库(R21NR018963- 01A1)。我们的目标是测试和表征TL和AD/ADRD之间的关系以及 相关测量的样本量比以往任何一项研究都大得多。我们 将对目标语和认知功能进行关联和因果分析 大脑成像测量，使用横截面和纵向数据。父辈 GRANT不专注于AD/ADRD，主要目的是描述可修改的风险敞口 直接影响或调节TL，以及这些关系如何影响健康和 有患病的风险。申请者群体具有丰富的老龄工作经验 英国生物库(UKB)中的定向分析，包括脑MRI数据。此外，我们 包括David Steffens博士和Lihong Wang博士，以支持本附录的目标。 斯蒂芬斯博士是一名精神病学家，他的专长是对情绪进行定性 和老年抑郁症的认知结果，以及神经基础和 AD/ADRD的结果。王医生是一名神经科医生，她进行了神经成像。 老年抑郁症和认知功能减退患者的研究。两人都很熟悉 UKB痴呆症和影像数据。我们希望能深入了解两国关系 中间认知功能和脑成像在TL和AD/ADRD之间的作用 措施。我们的发现将建议大脑区域以减缓进展为目标 前往AD/ADRD。

Project Summary/Abstract Telomere attrition is a key aging hallmark. Telomeres are repetitive sequences of TTAGGG at the ends of chromosomes, shortening with age, and cells enter senescence states when telomeres reach a critically short length. Observational and genetic studies have shown that shorter telomere length (TL) in blood is associated with increased risk of Alzheimer’s disease (AD). However, the study sample sizes have been relatively small, with a 2016 meta-analysis including only 860 AD patients and 2,022 controls from 13 studies. There is increasing evidence that brain changes take place years before Alzheimer’s disease or its related dementias (AD/ADRD) are diagnosed. While the relationship between TL and AD/ADRD is possibly causal, associations between TL and cognitive function or decline are inconsistent and studies to test TL associations with brain imaging features are largely missing. To fill these gaps, we propose to use already available brain Magnetic Resonance Imaging (MRI) data from 100,000 participants in the UK Biobank building on our parent grant (R21NR018963- 01A1). We aim to test and characterize the relationship between TL and AD/ADRD and related measures with a much larger sample size than that of any previous study. We will conduct association and causation analyses on TL and cognitive function as well as brain imaging measures, using both cross-sectional and longitudinal data. The parent grant is not focused on AD/ADRD and aims mainly to delineate modifiable exposures that directly influence or moderate TL, and how the relationships influence health and risk of disease. The applicant group have extensive experience undertaking aging oriented analyses in UK Biobank (UKB), including the brain MRI data. Additionally, we include Drs. David Steffens and Lihong Wang to support the aims of this supplement. Dr. Steffens is a psychiatrist and his expertise has been the characterization of mood and cognitive outcomes in late life depression, as well as the neural basis and outcomes of AD/ADRD. Dr. Wang is a neurologist and she has conducted neuroimaging research in patients with late-life depression and cognitive decline. Both are familiar with UKB dementia and imaging data. We expect to gain insight into the relationship between TL and AD/ADRD via intermediate cognitive function and brain imaging measures. Our findings will suggest brain regions to target to slow the progression towards AD/ADRD.