Identifying potentially modifiable exposures to improve telomere health and disease outcomes

项目总结/文摘

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.