Mid-life leukocyte telomere length and dementia risk: a prospective cohort study of 435,046 UK Biobank participants

ImportanceTelomere attribution is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimers disease and Alzheimers disease related dementias (AD/ADRD). ObjectiveTo 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. Design, Setting, and ParticipantsData 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. ExposuresRelative mean leukocyte TL at baseline was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction technique by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). Main Outcomes and MeasuresAD/ADRD was confirmed by mapping multi-source data to 3-charcter ICD codes (G30; F00; F01; F03; G31), excluding other-cause dementias (F02). ResultsLonger TL was associated with a lower risk of incident AD/ADRD (adjusted HR [aHR] per SD=0.93, 95% CI 0.90 to 0.96, P=3.37x10-7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume (adjusted standardized {beta} [a{beta}] per SD=0.012, 95% CI 0.003 to 0.021, P=0.012), lower total volume of white matter hyperintensities (a{beta} per SD= -0.015, 95% CI -0.024 to -0.006, P=0.002), and higher fractional anisotropy (FA; a{beta} per SD=0.018, 95% CI 0.009 to 0.027, P=9.44x10-5) and lower mean diffusivity (MD; a{beta} per SD=0.045, 95% CI 0.035 to 0.056, P=1.07x10-17) in the fornix. Conclusions and RelevanceLonger TL is a protective factor against AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. A better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults. Key PointsO_ST_ABSQuestionC_ST_ABSIs leukocyte telomere length (TL) associated with Alzheimers disease (AD) and AD related dementias (AD/ADRD) and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging phenotypes? FindingsLonger TL was associated with a lower risk of incident AD/ADRD, larger hippocampus volume, lower total volume of white matter hyperintensities, higher fractional anisotropy and lower mean diffusivity in the fornix. MeaningLonger TL in midlife may play a protective role against AD/ADRD, and a better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults.