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Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants |
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| Authors: | Rui Liu Meiruo Xiang Luke C Pilling David Melzer Lihong Wang Kevin J Manning David C Steffens Jack Bowden Richard H Fortinsky George A Kuchel Taeho G Rhee Breno S Diniz Chia-Ling Kuo |
| Institution: | 1. Department of Health Sciences, Sacred Heart University, Fairfield, Connecticut, USA;2. Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, Connecticut, USA;3. Epidemiology and Public Health Group, College of Medicine and Health, University of Exeter, Exeter, UK;4. Department of Psychiatry, University of Connecticut Health, Farmington, Connecticut, USA;5. Exeter Diabetes Group (ExCEED), College of Medicine and Health, University of Exeter, Exeter, UK;6. UConn Center on Aging, University of Connecticut Health, Farmington, Connecticut, USA;7. Department of Psychiatry, University of Connecticut Health, Farmington, Connecticut, USA
Department of Public Health Sciences, University of Connecticut Health, Farmington, Connecticut, USA;8. Department of Psychiatry, University of Connecticut Health, Farmington, Connecticut, USA UConn Center on Aging, University of Connecticut Health, Farmington, Connecticut, USA |
| Abstract: | Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio aHR] per SD = 0.93, 95% CI 0.90–0.96, p = 3.37 × 10−7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies. |
| Keywords: | Alzheimer's disease brain magnetic resonance imaging cognition hallmarks of biological aging vascular dementia |